Abstract
Graphical abstract
Abstract
Rett syndrome (RTT), a monogenic neurodevelopmental disorder mainly affecting female, is caused by mutations in X-linked MECP2 gene, an ubiquitous epigenetic regulator. In addition to neurological issues, RTT patients show a variety of multisystem manifestations and impairment of different signalling and metabolic pathways, including compromised mitochondrial function, altered redox homeostasis, improper cholesterol metabolism and subclinical inflammation. The sirtuin family (SIRTs), comprising seven members, catalyses the NAD+-dependent deacetylation, ADP-ribosylation and deacylation of a wide range of targets and works as sensors of cellular energetic status. In addition, SIRTs can modulate activities and gene expression of proteins involved in cellular stress responses related to oxidative stress, mitochondrial dysfunctions and inflammation, in both physiological and pathological conditions. Given some shared molecular aspects, herein, we revised the current scientific literature and hypothesized the possible relationship of SIRTs signalling involvement in RTT pathogenesis and OxInflammation. Although further research is needed, uncovering the possible involvement of SIRTs in RTT could reveal new potential pharmacological targets for the disorder. In light of this, SIRT-enhancing compounds could likely represent a new option to be tested as co-adjuvant alternatives to the current therapies.
Introduction
Rett syndrome (RTT) is a genetically defined neurodevelopmental pathology, primarily caused by mutations in the methyl-CpG-binding protein 2 (MECP2). Patients affected by RTT suffer from both neurologic (i.e. microcephaly, intellectual disability, seizures, absent or very limited speech) and non-neurologic manifestations (i.e. breathing, gastrointestinal and cardiac problems and recurrent infections), which make this syndrome a broad-spectrum pathology (Gold et al. 2018). In addition, at molecular level, RTT is characterized by an alteration of several metabolic traits, such as redox homeostasis, mitochondrial bioenergetics, cholesterol metabolism and inflammatory responses (Sticozzi et al. 2013, Segatto et al. 2014, Pecorelli et al. 2016a, Shulyakova et al. 2017).
Sirtuins (SIRTs) are a family of evolutionarily conserved enzymes, whose deacetylating function is mainly dependent on NAD+/NADH ratio. Therefore, these enzymes may serve as sensors of cellular energetic condition (Imai et al. 2000). Not only this, SIRTs play critical roles in the regulation of cellular homeostasis, in particular oxidative stress, inflammation, metabolism and senescence (Vachharajani et al. 2016, Singh et al. 2018, Lee et al. 2019). Different studies reported that activation of SIRTs may be helpful in metabolic diseases such as obesity and type 2 diabetes, as well as in ageing and neurological disorders (Rahman & Islam 2011).
Given some shared molecular aspects, herein, we attempted to summarize current knowledge on SIRTs in RTT. Our work aimed at stimulating researchers to deepen the role of SIRTs in this complex syndrome, in light of the likely involvement of these deacetylases in RTT and the potential beneficial effect of SIRT activators as possible co-adjuvants of the current therapies.
Rett syndrome
Rett syndrome (OMIM #312750) is a complex neurodevelopmental disorder, which mainly affects the female gender with an incidence rate ranging from 1:10,000 to 1:15,000 live births. Although considered a rare disease, RTT is the second most common cause of severe intellectual disability in females after Down syndrome (Neul et al. 2010).
After a period of normal development (6–18 months of life), RTT patients typically experience stagnation and rapid deterioration of the acquired psychomotor skills, leading to a distinctive clinical phenotype, characterized by severe intellectual disability, microcephaly, repetitive hand movements, seizures, absent or very limited speech, irregular breathing, cardiac abnormalities, ataxia and autistic features (Chahrour & Zoghbi 2007).
RTT was first described by Doctor Andreas Rett in 1966 (Rett 1966); however, only in 1999, Zoghbi’s group could identify the genetic source of the disease (95% of the cases), uncovering mutations in the X-linked MECP2 gene in RTT patients (Amir et al. 1999). The majority of RTT mutations occur in MECP2 exons 3 and 4, which consist of 4 key functional domains in the translated protein: a methyl-binding domain, a transcriptional repressor domain, an NCoR-interaction domain and a C-terminal domain, important for MeCP2 DNA-binding ability (Kyle et al. 2018). According to recent prediction algorithms, based on a FAIRification (Findable, Accessible, Interoperable, and Reusable) workflow, to date, more than 800 unique confirmed RTT-causing mutations in MECP2 have been identified (Ehrhart et al. 2021). However, eight missense and nonsense ‘hotspot’ mutations (R106W, R133C, T158M, R306C, R168X, R255X, R270X and R294X) are responsible for approximately 78% of total cases of RTT, and C-terminal deletions and large deletions are responsible for another 8% and 5%, respectively (Christodoulou et al. 2003). The type and location of the mutations are known to modulate clinical severity, hence, contributing to the high phenotypic variability observed in the disorder (Cuddapah et al. 2014).
MeCP2 is a nuclear protein, ubiquitously expressed throughout all human tissues and thanks even to its intrinsically disordered (ID) nature, MeCP2 plays multifunctional roles: it is implicated in the transcriptional regulation of numerous genes (by both activating and repressing transcription), chromatin organization, microRNA processing and RNA splicing (Ip et al. 2018).
In the CNS, MeCP2 is expressed at low levels prenatally but rises progressively during synaptogenesis and neuronal maturation with a maximum in mature, post-migratory neurons, suggesting a role for MeCP2 in sustaining neuronal activity, maturation and plasticity (Bedogni et al. 2016).
As already mentioned, the symptomatic hallmarks of RTT are mainly neurological and are associated with reduced brain volume, abnormally small neuronal body size and densely packed neurons, presenting decreased dendritic complexity and spine density particularly in cerebral cortex, thalamus, substantia nigra, basal ganglia, amygdala, cerebellum and hippocampus (Armstrong et al. 1995, Carter et al. 2008).
However, in the last few years, a multifaceted clinical appearance with variety of co-morbidities involving other tissues and organs have been identified in RTT patients, including sleep disturbances, periodic breathing disorder, electrocardiograms with prolonged cardiac QT interval, osteopenia, endocrine alterations, gastrointestinal problems, dysphagia, recurrent infections (especially at gallbladder, urinary and respiratory tract) or unexplained augment of fever (Borloz et al. 2021, Wang et al. 2021). In addition, from a molecular point of view, RTT patients exhibit deregulations of signalling and metabolic pathways, such as abnormal mitochondrial bioenergetics, unbalanced redox homeostasis, perturbed lipid metabolism and compromised immune-inflammatory responses (Segatto et al. 2014, Filosa et al. 2015, Shulyakova et al. 2017, Pecorelli et al. 2020a ). This topic will be better deepened in the next section (‘Oxidative stress and inflammation (‘OxInflammation’) in Rett syndrome pathogenesis).
Taken together, the combination of all these alterations can help to explain the complex nature of RTT, which is now increasingly considered a broad-spectrum pathology with multisystem disturbances (Borloz et al. 2021).
Oxidative stress and subclinical inflammation (‘OxInflammation’) in Rett syndrome pathogenesis
Despite advances in understanding the role of MeCP2, it is still unclear how the mutation of a single protein leads to all the manifestations mentioned in the previous section. Patients with RTT even present an impairment of signalling and metabolic pathways, like dysfunctional mitochondria, compromised redox homeostasis and chronic subclinical inflammatory status, which act in a vicious loop termed ‘OxInflammation’ (Pecorelli et al. 2016a ).
In particular, several papers reported increased levels of 4-hydroxynonenal protein adducts (4-HNE-PAs) and non-protein-bound iron (NPBI) in the systemic compartment of RTT subjects (De Felice et al. 2009, Pecorelli et al. 2011). Fibroblasts and peripheral blood mononuclear cells (PBMCs) derived from RTT patients showed increased levels of hydrogen peroxide (H2O2), mitochondrial reactive oxygen species (ROS) and 4-HNE-PAs (Cervellati et al. 2015, Cordone et al. 2022), in parallel with an alteration of the main antioxidant enzymes (i.e. glutathione reductase, thioredoxin reductase and glutathione peroxidase) and higher levels of oxidized glutathione (Signorini et al. 2014, Cervellati et al. 2015), as compared to cells isolated from control subjects.
In addition, RTT patients showed a dysregulation of acute phase response proteins, augmented levels of the bioactive lipid metabolite 13-hydroxyoctadecadienoic acid (13-HODE) and a perturbed cytokine profile, characterized by high serum levels of interleukin (IL)-3, IL-8, IL-9, IL-13 and IL-15 and a Th2-shifted balance (Cortelazzo et al. 2014, Leoncini et al. 2015, Pecorelli et al. 2016b , 2019). Other studies on both primary fibroblasts and PBMCs evidenced a deregulated NLRP3 inflammasome response (Pecorelli et al. 2020b , Cordone et al. 2022), an intracellular multi-protein complex assembled in response to different stimuli (both pathogens and sterile stressors, like ROS, cardiolipin and mitochondrial dysfunction) and characterized by the activation of inflammatory caspase 1, able to activate the pro-inflammatory cytokines IL-1β and IL-18 or cleave gasdermin D, leading to a pro-inflammatory form of cell death, known as pyroptosis (Broz & Dixit 2016). Macrophage populations, including microglia, are even deregulated in Mecp2-null mice (Cronk et al. 2015). Intriguingly, brains of pre-phenotypic and phenotypic RTT mice (Mecp2 knock-out and Mecp2 308) exhibit signs of oxidative stress and related damages, together with an impaired expression of genes associated with innate immunity already before the appearance of the typical symptoms (De Felice et al. 2014, Bebensee et al. 2017, Zhao et al. 2017, Adebayo et al. 2020, Cortelazzo et al. 2020). As corroborating findings, systemic levels of IL-18, 4-HNE and F2-dihomo-isoprostanes were enhanced mostly in the early stages of the disease (De Felice et al. 2011, Pecorelli et al. 2011, Cordone et al. 2022), suggesting that the vicious circle of OxInflammation can take part in both RTT pathogenesis and progression (Valacchi et al. 2018).
Sirtuins as defensive mechanisms
SIRTs are a family of conserved enzymes, initially classified as histone deacetylases (HDACs), that are able to deacetylate a variety of target proteins besides histones (Imai et al. 2000). In a lesser extent, they also catalyse mono-ADP ribosylation of protein acceptors and deacylation, by hydrolysing lysines modified with longer acyl chains (Zhao et al. 2004, Feldman et al. 2013). Unlike the zinc-related class I, II and IV HDACs, SIRTs use NAD+ as a co-factor to exert their activity. Considering the importance of the fine-regulated balance of NAD+/NADH ratio, SIRTs may serve even as sensors of the cellular energy status (Imai & Guarente 2016).
In mammals, seven paralogs have been identified (SIRT1–7). The seven mammalian SIRTs vary in sequence (especially, the terminal aminoacidic structure, which is responsible for the different subcellular localizations; however, they possess a conserved catalytic core), enzyme activity, substrate specificity and cell functions, like metabolism, genome maintenance and stress responses. Although new in vivo specificities and targets are reported every day, in Table 1 are summarized the main functions and effects of SIRTs in human cells.
Summary of the main functions and effects of SIRTs in human cells.
| SIRT isoform | Catalytic activity | Subcellular localization | Target proteins | Cellular functions |
|---|---|---|---|---|
| SIRT1 | Deacetylase | Nucleus Cytoplasm |
p53, H3K9, H1K26, H4K16, PGC1α, SREBP-1c, PPARγ NF-κB, AKT, FOXOs, HIF-1α, TFAM, AceCS1, APE1, and PARP-1 | ↓ Inflammation ↓ Oxidative stress ↓↑ Gluconeogenesis ↓ Lipogenesis ↑ Lipolysis |
| SIRT2 | Deacetylase Demyristoylase |
Cytoplasm | PEPCK, α-tubulin, H4K16, and FOXO3a, NLRP3 | ↑ Gluconeogenesis Control of mitotic exit |
| SIRT3 | Deacetylase | Mitochondria | LCAD, HMGCS2, SOD2, IDH2, PDC, AceCS2, OGG1, OPA1, LONP1, FOXO3a/PINK1/PARKIN | ↓ Lipid accumulation ↑ Fatty acid oxidation ↑ Ketone body production ↑ Mitogenesis ↑ Mitophagy ↑ mtUPR ↑ Glutamine catabolism ↓ Oxidative stress |
| SIRT4 | ADP-ribosyltransferase Lipoamidase |
Mitochondria | GDH, PDC, MCD, OPA1 | ↓ Insulin secretion ↓ Fatty acid oxidation ↓ Mitogenesis ↓ Mitophagy ↓ Glutammine catabolism |
| SIRT5 | Desuccinylase Demalonylase Deglutarylase |
Mitochondria | CPS1, IDH2, SOD1 | ↑ Urea cycle ↑ Ketogenesis ↓ Oxidative stress |
| SIRT6 | Deacetylase Depalmitoylase Demyristoylase ADP-ribosyltransferase |
Nucleus Cytoplasmic reticulum |
H3K9, H3K56, TNFα, PARP-1, GCN5, and HIF-1α | ↓ Glucose uptake ↑ Inflammation ↑ DNA reparation |
| SIRT7 | Deacetylase ADP-ribosyltransferase |
Nucleolus | PAF53, H3K18, OSX | ↑ RNA polymerase I transcription ↑ Bone formation |
AceCS, acetyl-CoA synthetase; AKT, protein kinase B; APE1, apurinic/apyrimidinic endonuclease 1; CPS1, carbamoyl-phosphate synthase 1; FOXOs, forkhead box proteins; GCN5, histone acetyltransferase; GDH, glutamate dehydrogenase; HIF-1α, hypoxia-inducible factor 1 alpha; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; IDH2, isocitrate dehydrogenase 2; LCAD, long-chain acyl-CoA dehydrogenase; LONP1, LON protease; MCD, malonyl-CoA decarboxylase; mtUPR, mitochondrial unfolded protein response; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; OGG1, 8-oxoguanine-DNA glycosylase 1; OPA1, GTPase optic atrophy 1 protein; OSX, SP7/Osterix; PAF53, RNA polymerase associated factor; PARP-1, poly(ADP-ribose) polymerase 1; PDC, pyruvate dehydrogenase complex; PEPCK, phosphoenolpyruvate carboxykinase; PGC1α, peroxisome proliferator-activated receptor gamma co-activator 1 alpha; PINK1, PTEN-induced kinase 1; PPARα, peroxisome proliferator-activated receptor alpha; PPARγ, peroxisome proliferator-activated receptor gamma; SOD, superoxide dismutase; SREBP-1c, sterol regulatory element binding protein c; TFAM, mitochondrial transcription factor A; TNFα, tumor necrotic factor alpha; UCP-2, uncoupling protein 2.
SIRTs with different subcellular localizations can influence the spatial control of protein post-translational modifications (PTMs). SIRT3–5 are mitochondrial proteins (mtSIRTs) that are thought to have a key role in coordinating essential aspects of mitochondrial function (Di Emidio et al. 2021). Whereas, SIRT1, the most studied human isoform, is able to shuttle between nucleus and cytoplasm and regulate other essential physiological processes, linked to chronic inflammatory pathologies and metabolic dysfunctions such as obesity, diabetes, ageing and ageing-related disorders and cancer (Rahman & Islam 2011).
Sirtuins role in redox homeostasis and mitochondrial function
Evidence from scientific literature shows that almost all the known mammalian sirtuins may be directly or indirectly associated with oxidative stress and antioxidant cell defence (Singh et al. 2018). For example, the action of SIRT1 is mainly mediated by redox-linked transcription factors, like FOXOs and p53. Forkhead box (FOXO) proteins are responsible for the regulation of stress resistance, energy metabolism, cell cycle and cell death (Du & Zheng 2021). Several studies reported that SIRT1 and SIRT2 are able to deacetylate FOXO proteins, thus inducing their nuclear translocation, enhancing their DNA-binding ability and activating the transcription of different FOXO-dependent antioxidant genes in mitochondria (i.e. peroxiredoxins 3 and 5 and superoxide dismutase (SOD) 2), peroxisomes (i.e. catalase) and plasma (i.e. ceruloplasmin and selenoprotein P), as well as other stress resistance genes, including β-catenin and growth arrest and DNA damage-inducible 45 (Gadd45) (Brunet et al. 2004, Wang et al. 2007, 2017, Hughes et al. 2011, Nakagawa & Guarente 2011, Krafczyk & Klotz 2022). Interestingly, knocking down FOXO1 leads to a decrease of SIRT1 expression in HEK293 and vascular smooth muscle cells, suggesting a positive feedback loop for SIRT1 activity (Xiong et al. 2011).
SIRT1 can also prevent the formation of ROS by inhibiting nuclear factor-κB (NF-κB) translocation into the nucleus and reducing the gene expression of GP91 PHOX and P22 PHOX , which are part of NADPH oxidase enzyme (Salminen et al. 2013, Zarzuelo et al. 2013, Zhu et al. 2014). The control of ROS production by SIRT1 can be even due to its effect on mitochondrial electron transport chain (ETC); indeed, the activation of SIRT1, by SRT1720, restored the expression of some ETC proteins, like ATPβ, NDUFB8 and cytochrome c oxidase subunit I (COX I) in an intracerebral haemorrhage (ICH) mouse model (Zhou et al. 2017).
As known, mitochondria is the main site of ROS production and also the hub of various metabolic pathways such as oxidative phosphorylation (OXPHOS), β-oxidation of fatty acids, tricarboxylic acid cycle and urea cycle (Di Emidio et al. 2021). Peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), a master regulator of mitochondrial biogenesis and oxidative metabolism, represents one of the key targets of SIRT1 involvement in mitochondrial function (Gurd 2011, Guo et al. 2014). Indeed, SIRT1 can regulate the acetylation state and activity level of PGC-1α, which can rapidly translocate into the nucleus and co-activate the nuclear respiratory factors (NRFs), nuclear receptor peroxisome proliferator-activated receptor, estrogen-related receptor and mitochondrial transcription factor A (TFAM) to control the expression of key genes for respiration, metabolism of glucose and lipids, mtDNA transcription and mtDNA replication machineries (Rodgers et al. 2005, Ventura-Clapier et al. 2008).
About mitochondrial functions, a particular attention should be paid to mtSIRTs. SIRT3, in particular, has been demonstrated to promote mitochondrial respiration and OXPHOS, by its deacetylating action on all ETC complexes, which can facilitate the electron flow and ATP production (Finley et al. 2011, Wu et al. 2013, Rahman et al. 2014, van de Ven et al. 2017). SIRT3 is able to directly deacetylate and activate SOD2, the primary scavenger of superoxide anion (Tao et al. 2010). Recently, it has been shown that SIRT3 plays a role in the regulation of mitochondrial quality control and in preventing the accumulation of damaged mitochondria. SIRT3 may indeed activate the mitochondrial unfolded protein response (mtUPR), thus inducing alterations in mitochondrial fission, fusion and mitophagy (Meng et al. 2019). In particular, SIRT3 is able to activate the Lon protease P1 by deacetylation, leading to the degradation of mitochondrial oxidized proteins (Gibellini et al. 2014). The complex mechanism of cellular control of the redox milieu is even regulated by SIRT5. Lin et al. (2013) found that the increased SOD1 activity in reducing superoxide anions was due to SIRT5-dependent desuccinylation of Lys123 (Lin et al. 2013).
Taken together, sirtuins, especially SIRT1 and mtSIRTs, increasingly represent a fascinating research topic in both physiological and pathological conditions, given the strict link between them and redox homeostasis and mitochondrial metabolism/function.
Sirtuins role in inflammatory pathways
A number of works elucidated the role of SIRTs, in particular SIRT1, in mediating different stress responses, including inflammation, heat shock and hypoxic stress (Vachharajani et al. 2016). SIRT1 can reduce inflammation through its effect on nuclear factor-κB (NF-κB); indeed, SIRT1 is able to interact and deacetylate the p65 subunit/RelA at Lys310 residue, thus inhibiting NF-κB activity (Yeung et al. 2004). Treatment with resveratrol, one of the most studied SIRT1 agonists, inhibited NF-κB and ROS build-up in tumor necrosis factor (TNF)-α-stimulated HUVEC cells (Pan et al. 2016). On the other hand, NF-κB signalling may in turn suppress SIRT1 activity through the expression of miR-34a, interferon (IFN)-γ and ROS, thus determining a negative feedback regulation of SIRT1 and stimulating the NF-κB-related inflammatory response typical of chronic, metabolic and age-linked diseases (Kauppinen et al. 2013). During acute inflammation, several steps aimed at eliminating the cause of tissue injury and restoring the immune homeostasis. Innate immune cells express different types of receptors, including toll-like receptors (TLRs) able to sense and bind pathogen-associated molecular patterns (PAMPs). Once activated by PAMPs, TLRs rapidly trigger the expression and transcriptional activation of hypoxia inducible factor 1 subunit alpha (HIF-1α), which can switch mitochondrial OXPHOS towards aerobic glycolysis and enhance glucose levels to support the expression of pro-inflammatory genes, like IL-12, IL-1A and TNF-A (Koo & Garg 2019). The switching from a pro-inflammatory to an immuno-regulatory or anti-inflammatory state requires a transcriptional change, regulated by SIRT1-related deacetylation of NF-κB and histones (i.e. H1K26, H3K9, H3K14 and H4K16) and the enrolment of new methyltransferases (Liu & McCall 2013). In addition, SIRT1 may participate in counteracting acute inflammatory responses by mediating PGC-1α activation and promoting fatty acid oxidation as mitochondrial energy source, hence inducing a metabolic switch (Liu & McCall 2013, Koo & Garg 2019). A state of chronic inflammation is caused by persistent low-level stimuli that can be both pathogenic and non-pathogenic. A downregulation of SIRT1 activity is reported in a variety of diseases with an important chronic inflammatory component, including obesity, chronic obstructive pulmonary disease, Alzheimer’s and Parkinson’s disease, atherosclerosis and ageing (Rahman et al. 2012, Chun 2015, Kitada et al. 2016, Gomes et al. 2018, Pardo & Boriek 2020, Fernando & Wijayasinghe 2021). Besides the reduced shut down of NF-κB-dependent gene expression of pro-inflammatory molecules, the mechanisms linking SIRT1 decline to chronic inflammation are not fully understood. However, enhancing NAD+ levels or activating SIRT1 could likely decrease chronic inflammation and help establish metabolic homeostasis (De Sá Coutinho et al. 2018).
Growing evidence suggests a role for SIRT1 in the inflammatory responses in CNS (Jiao & Gong 2020). It has been shown that the SIRT1 activator resveratrol reduced the secretion of IL-6 and TNF-α in microglial BV2 cells upon lipopolysaccharides (LPS) challenge, while the inhibition of SIRT1 through sirtinol and EX-527 induced, respectively, the release of inflammatory factors in the same cells, and the upregulation of gene expression levels of TNF-A and IL-1B and ROS generation in astrocytes, after LPS stimulation (Ye et al. 2013, Cheng et al. 2014).
In the last 4 years, a growing body of literature indicates a new potential regulatory mechanism of SIRT1 on NLRP3 inflammasome response in the neuroinflammation involved in several pathologies. In specific, it has been suggested that SIRT1 activators could inhibit the inflammatory cytokine production of IL-1β, IL-18 and TNF-α via the inhibition of NLRP3 inflammasome response (He et al. 2017, Zou et al. 2018, Han et al. 2020, Shaheen et al. 2021, Xia et al. 2021, Zheng et al. 2021). Besides SIRT1, also SIRT3 seems to be linked to neuroinflammation and NLRP3 inflammasome; indeed, a comprehensive acetylome analysis revealed that SIRT3 deficiency can lead to microgliosis, brain mitochondrial dysfunction, increased caspase-1 cleavage and IL-1B gene expression levels, thus suggesting a role of this mtSIRT in late-life cognitive decline (Tyagi et al. 2018).
Taken together, SIRTs are important for their action in response to various inflammation-related stress and to organize the survival signals trying to counteract these stressors.
Sirtuins in neurological diseases
As recently reviewed, SIRTs are crucial, at different molecular levels, for the regulation of neuronal cell death and the pathology of neurodegenerative diseases, like Alzheimer’s and Parkinson’s diseases, multiple sclerosis and amyotrophic lateral sclerosis (Manjula et al. 2020, Bhatt & Tiwari 2022, Leite et al. 2022). Several studies revealed that SIRT1 and 3 expression is reduced in the brain of patients with Alzheimer’s disease (Lutz et al. 2014, Yin et al. 2018). In particular, besides the role of SIRTs in mitochondrial dysfunction, oxidative stress and neuroinflammation (mainly through the involvement in NF-κB signalling and inflammasome pathways), SIRTs can regulate the processing of amyloid precursor protein (APP) by promoting the formation of non-amyloidogenic soluble APPα and the deacetylation of tau protein resulting in an attenuation of its accumulation and toxicity (Manjula et al. 2020).
Moreover, of note, an efficient control of NAD+/NADH ratio is necessary for the proper functioning of mitochondrial bioenergetic processes and for SIRTs enzymatic activity. For example, NAD+ hydrolases such as sterile alpha and TIR motif containing 1 (SARM1) can modulate SIRTs activation and contribute to axonal degeneration and NAD+ depletion (Gerdts et al. 2015).
Several studies reported an impaired energy metabolism and a reduced NAD+/NADH ratio even in patients affected by the neurodevelopmental and neuropsychiatric disorders, such as autism, schizophrenia and bipolar disorder (Boccuto et al. 2013, Kim et al. 2017, Jeong et al. 2020).
Possible role of sirtuins in Rett syndrome
Despite SIRTs action influencing several cellular metabolic and OxInflammatory aspects, involved in RTT pathogenesis, to date, only a few literature papers investigated the possible link between this class of enzymes in the disease.
Zocchi and Sassone-Corsi (2012) first demonstrated that SIRT1 is able to deacetylate MeCP2 at Lys464, in both in vitro and in vivo assays. In particular, the treatment with SIRT1-inhibitor EX-527 significantly augmented the acetylated state of MeCP2 in HEK-293 cells, uncovering the specificity of interaction between MeCP2 and SIRT1 but not the other members of the SIRTs family. Moreover, MeCP2 recruitment on the brain-derived neurotrophic factor (BDNF) promoter was higher in SIRT1Δex4 (lacking the catalytic domain) mice, resulting in a decrease of BDNF protein and mRNA levels. These data suggest that SIRT1-dependent action on MeCP2 allows its release from the BDNF promoter, thus leading to increased BDNF transcription (Zocchi & Sassone-Corsi 2012). Accordingly, resveratrol has been found to induce an increase of BDNF in developing mice exposed to sevoflurane (an anaesthetic toxic during neonatal exposure), corroborating the role of SIRT1 as a crucial player in synaptic plasticity and cognitive performance (Tang et al. 2020).
In addition, a recent work has showed a reduction of miR-199a in mouse Mecp2-KO neurons and neural stem cells (NSCs), which seems relevant to RTT pathophysiology due to its positive regulation of mammalian target of rapamycin (mTOR) signalling. miR-199a is able to inhibit Pde4d, Sirt1 and Hif-1α downstream of MeCP2 (Tsujimura et al. 2015).
SIRT1 is even implied in regulating the expression of the neuron-specific K+/Cl− cotransporter 2 (KCC2), which has been found to be reduced in human RTT neurons and in RTT mouse models (Tang et al. 2016). KCC2 plays a pivotal role in the maintenance of excitatory/inhibitory (E/I) balance, determining the polarity and efficacy of GABA inhibition, thus, it is a regulator of excitatory synapse development and dendritic spine morphogenesis (Li et al. 2007). Tang et al. (2019), by using a high-throughput drug screening platform, identified the activators of SIRT1 as KCC2 expression-enhancing compounds. They further demonstrated that resveratrol could effectively increase KCC2 expression in MECP2-null RTT human neurons (isogenic to the wild-type cells, derived from embryonic stem cells), hence, confirming the therapeutic benefit of SIRT1 activator on a number of brain diseases and likely on RTT (Tang et al. 2019).
The acetylation state of microtubules plays key functions in increasing the fast axonal transport of BDNF and mitochondria and in recruitment and binding of kinesin-1 and dynein to the microtubules (Sferra et al. 2020). It was found that AGK2, a SIRT2-specific inhibitor, can enhance the α-tubulin acetylation and the subsequent activation of NLRP3 inflammasome complex in macrophages (Misawa et al. 2013). Specifically, SIRT2, by its deacetylating action on α-tubulin, can induce microtubule destabilization, thus preventing the approximation of mitochondria (presenting the adaptor protein ASC) towards the perinuclear area and endoplasmic reticulum, where NLRP3 is localized, and also avoiding the association of NLRP3 with mitochondrial products, such as oxidized mtDNA and cardiolipin (Misawa et al. 2013, Traba & Sack 2017). The acetylation state of α-tubulin seems to be altered in primary cultures of fibroblasts derived from two male RTT patients (Gold et al. 2015).
Moreover, He et al. (2020) revealed that NLRP3 is post-translationally modified by acetylation in macrophages, facilitating the activation of the inflammasome system, and is directly deacetylated by SIRT2. Hence, SIRT2 and NLRP3 deacetylation could be modulated to prevent ageing-associated and chronic inflammatory conditions (He et al. 2020). Besides SIRT2, SIRT1 is also implicated in regulating the activation of the NLRP3 inflammasome. Indeed, resveratrol is reported to both inhibit the accumulation of acetylated α-tubulin and activate AMP-activated protein kinase (AMPK), resulting in the induction of autophagy, which is involved in the switch-off of NLRP3 response (Chang et al. 2015, Misawa et al. 2015).
In this regard, we recently demonstrated that the assembly of NLRP3 machinery was increased in both RTT fibroblasts and PBMCs already at basal condition (Pecorelli et al. 2020b , Cordone et al. 2022). We could hypothesize that an impairment of SIRT1 or SIRT2 may be involved, together with high ROS levels and mitochondrial dysfunction, in the aberrant response of the inflammasome complex occurring in RTT, thus likely contributing to the inflammatory status typical of the pathology.
In addition, as previously mentioned, two of the main SIRT1 targets are NF-κB and PGC-1α, with the resulting suppression of p65 binding to promoter regions of several pro-inflammatory genes, and the activation of PGC-1α downstream signalling, respectively. Several papers reported augmented NF-κB nuclear translocation and pro-inflammatory signalling in both in vitro and in vivo models of RTT (Kishi et al. 2016, Pecorelli et al. 2020b , Cordone et al. 2022). A downregulation of PGC-1α and NRF1, but not TFAM, was found in primary dermal fibroblasts of RTT patients (Cervellati et al. 2015). The same authors also demonstrated that RTT cells presented a reduced activity of both SOD1 and SOD2. As reported above, SOD1 and SOD2 PTMs and enhanced enzymatic activity are dependent directly on SIRT5 and SIRT3, respectively, and indirectly on SIRT1/FOXOs axis. Although they are just hypothesis, not yet mechanistically demonstrated in Rett syndrome, we could hypothesize that the OxInflammatory status occurring in RTT can likely be linked to an alteration of SIRTs functionality (Fig. 1).
Possible roles of SIRTs in pathogenesis and OxInflammatory status typical of Rett syndrome. (A) Resveratrol can induce an increase of K+/Cl− cotransporter 2 (KCC2) expression, an important regulator of excitatory synapse development and dendritic spine morphogenesis, whose expression is reduced in RTT; (B) an enhancement of SIRT1 could inhibit the aberrant NF-κB p65 signalling observed in RTT, by its deacetylating action; (C) SIRT1 can promote a transcriptional de-repression of BDNF, by deacetylating MeCP2 and inducing its release from BDNF promoter region; (D and E) a positive modulation of SIRT2 on one hand could deacetylate microtubules, avoiding the approximation of mitochondria (presenting ASC) towards the perinuclear area and endoplasmic reticulum (presenting NLRP3), on the other hand could directly deacetylate NLRP3, preventing the constitutive inflammasome activation reported in RTT; (F and G) SIRT1 activators could inhibit the activation of inflammasome complex of RTT cells, by several indirect mechanisms, like reducing ROS or stimulating the AMPK-dependent autophagy; (H) an increased activity of SIRT3 could reduce mitochondrial ROS levels, by inducing the deacetylation of SOD2, and increasing its activity, which is impaired in several RTT cellular models.
Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0004
Sirtuins in autism spectrum disorders
Finally, considering that RTT has been classified as part of the autism spectrum disorders (ASD) up to May 2013, due to its autistic-like symptomatology, the possible involvement of sirtuins in ASD is summarized in the following section.
ASD has a high prevalence rate in children, influences neurodevelopment, and leads to social and communication impairments. ASD is considered as a complex disease, being determined by both genetic and environmental components (Bai et al. 2019). A study by Bu et al. (2017) evaluated the function of SIRT1/PGC-1α axis in the oxidative stress condition of ASD. They found that both gene and protein expression levels of SIRT1 and PGC-1α were reduced in lymphoblastoid cell lines (LCLs) derived from ASD patients. While the over-expression of PGC-1α, through plasmid cell transfection, inhibited ROS production and LCL apoptosis, suggesting that the improvement of PGC-1α activity could decrease the oxidative injury in ASD LCLs, thus making this transcription co-activator a likely target for future treatments (Bu et al. 2017).
Despite some controversial findings (Bennuri et al. 2019, Smedler et al. 2021), the effect of resveratrol has been assessed in several ASD mouse models, exhibiting increased anti-oxidative (i.e. decreased lipid peroxidation levels) and anti-inflammatory (i.e. reduced levels of IL-6, IFN-γ, TNF-α and pJAK1; ameliorated dysregulation of Th1, Th2 and Th17) responses in treated animals (Bakheet et al. 2017, Bhandari & Kuhad 2017, Ahmad et al. 2018). Recently, Hendouei et al. (2020) tested resveratrol in an early-stage clinical trial: specifically, the molecule was used as a co-adjuvant of risperidone therapy (a drug able to rebalance dopamine and serotonin to improve mood, thinking and behaviour) in a double-blind, randomized clinical trial. Although the authors have not observed significant differences between the two groups (resveratrol + risperidone and placebo + risperidone) in ameliorating irritability and other ASD-associated symptoms such as social and communication skills, the patients treated with resveratrol showed decreased signs of hyperactivity, as compared to risperidone alone (Hendouei et al. 2020).
Despite the promising results of SIRTs activators, the molecular mechanisms and the role played by these deacetylases in the development and treatment of ASD need further investigations.
Conclusions
Extensive research within the past decades revealed that SIRTs family is implied in metabolic diseases, ageing and neurological disorders. At a molecular level, a positive modulation of SIRTs can be neuroprotective and counteract conditions of altered redox homeostasis and chronic, low-grade inflammation, which are common denominators of these pathologies and even RTT. For example, resveratrol, SRT1720 and SRT2104, some common SIRT1 activators, were found to have a broad-spectrum antioxidant and anti-inflammatory effects, as well as to reduce levels of protein carbonylation and formation of 4-HNE-PAs in pre-clinical studies of different diseases (Mercken et al. 2014, De Sá Coutinho et al. 2018). In addition, resveratrol treatment was able to modulate neuroinflammation and slow down functional and cognitive decline of subjects with mild-moderate Alzheimer’s disease (Moussa et al. 2017). Thanks to its safety and tolerability up to 5 g/day in healthy individuals (Patel et al. 2011), the natural compound resveratrol may represent a promising candidate for further testing in clinical trials of neurodegenerative disorders and, maybe, for starting in vitro and pre-clinical studies in RTT.
Honokiol, a poly-phenolic molecule and SIRT3 activator, even showed neuroprotective properties, enhanced antioxidant activity and mitochondrial function, through activating mitophagy and mtUPR in animal models of Alzheimer’s and Parkinson’s diseases (Chen et al. 2018, Li et al. 2018, Hou et al. 2022), which makes this compound another likely candidate to be investigated in trying to counteract mitochondrial alterations typical of RTT.
Taken together, although further research is needed, our hypotheses suggest that an alteration of SIRTs could take part in the OxInflammation typical of RTT, and both natural and chemical SIRT-enhancing compounds could represent a new option to be tested as co-adjuvant alternative to the current therapies.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
V C and G V conceived the study. V C wrote the paper with support of A P. G V contributed to the final version of the manuscript.
References
Adebayo OL, Dewenter I, Rinne L, Golubiani G, Solomonia R & Müller M 2020 Intensified mitochondrial hydrogen peroxide release occurs in all brain regions, affects male as well as female Rett mice, and constitutes a life-long burden. Archives of Biochemistry and Biophysics 696 108666. (https://doi.org/10.1016/j.abb.2020.108666)
Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Alzahrani MZ, Alshammari MA, Alanazi WA, Alasmari AF & Attia SM 2018 Resveratrol attenuates pro-inflammatory cytokines and activation of JAK1-STAT3 in BTBR T+ Itpr3tf/J autistic mice. European Journal of Pharmacology 829 70–78. (https://doi.org/10.1016/j.ejphar.2018.04.008)
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U & Zoghbi HY 1999 Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics 23 185–188. (https://doi.org/10.1038/13810)
Armstrong D, Dunn JK, Antalffy B & Trivedi R 1995 Selective dendritic alterations in the cortex of Rett syndrome. Journal of Neuropathology and Experimental Neurology 54 195–201. (https://doi.org/10.1097/00005072-199503000-00006)
Bai D, Yip BHK, Windham GC, Sourander A, Francis R, Yoffe R, Glasson E, Mahjani B, Suominen A & Leonard H et al.2019 Association of genetic and environmental factors with autism in a 5-country cohort. JAMA Psychiatry 76 1035–1043. (https://doi.org/10.1001/jamapsychiatry.2019.1411)
Bakheet SA, Alzahrani MZ, Ansari MA, Nadeem A, Zoheir KMA, Attia SM, Al-Ayadhi LY & Ahmad SF 2017 Resveratrol ameliorates dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in a BTBR T + tf/J mouse model of autism. Molecular Neurobiology 54 5201–5212. (https://doi.org/10.1007/s12035-016-0066-1)
Bebensee DF, Can K & Müller M 2017 Increased mitochondrial mass and cytosolic redox imbalance in hippocampal astrocytes of a mouse model of Rett syndrome: subcellular changes revealed by ratiometric imaging of JC-1 and roGFP1 fluorescence. Oxidative Medicine and Cellular Longevity 2017 3064016. (https://doi.org/10.1155/2017/3064016)
Bedogni F, Cobolli Gigli C, Pozzi D, Rossi RL, Scaramuzza L, Rossetti G, Pagani M, Kilstrup-Nielsen C, Matteoli M & Landsberger N 2016 Defects during Mecp2 null embryonic cortex development precede the onset of overt neurological symptoms. Cerebral Cortex 26 2517–2529. (https://doi.org/10.1093/cercor/bhv078)
Bennuri SC, Rose S & Frye RE 2019 Mitochondrial dysfunction is inducible in lymphoblastoid cell lines from children with autism and may involve the TORC1 pathway. Frontiers in Psychiatry 10 269. (https://doi.org/10.3389/fpsyt.2019.00269)
Bhandari R & Kuhad A 2017 Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. Neurochemistry International 103 8–23. (https://doi.org/10.1016/j.neuint.2016.12.012)
Bhatt V & Tiwari AK 2022 Sirtuins, a key regulator of ageing and age-related neurodegenerative diseases. International Journal of Neuroscience 1–26. Online ahead of print (https://doi.org/10.1080/00207454.2022.2057849)
Boccuto L, Chen CF, Pittman AR, Skinner CD, McCartney HJ, Jones K, Bochner BR, Stevenson RE & Schwartz CE 2013 Decreased tryptophan metabolism in patients with autism spectrum disorders. Molecular Autism 4 16. (https://doi.org/10.1186/2040-2392-4-16)
Borloz E, Villard L & Roux JC 2021 Rett syndrome: think outside the (skull) box. Faculty Reviews 10 59. (https://doi.org/10.12703/r/10-59)
Broz P & Dixit VM 2016 Inflammasomes: mechanism of assembly, regulation and signalling. Nature Reviews: Immunology 16 407–420. (https://doi.org/10.1038/nri.2016.58)
Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R & Cohen HY et al.2004 Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303 2011–2015. (https://doi.org/10.1126/science.1094637)
Bu X, Wu D, Lu X, Yang L, Xu X, Wang J & Tang J 2017 Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder. Neuropsychiatric Disease and Treatment 13 1633–1645. (https://doi.org/10.2147/NDT.S129081)
Carter JC, Lanham DC, Pham D, Bibat G, Naidu S & Kaufmann WE 2008 Selective cerebral volume reduction in Rett syndrome: a multiple-approach MR imaging study. American Journal of Neuroradiology 29 436–441. (https://doi.org/10.3174/ajnr.A0857)
Cervellati C, Sticozzi C, Romani A, Belmonte G, De Rasmo D, Signorile A, Cervellati F, Milanese C, Mastroberardino PG & Pecorelli A et al.2015 Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage. Biochimica Et Biophysica Acta 1852 2066–2074. (https://doi.org/10.1016/j.bbadis.2015.07.014)
Chahrour M & Zoghbi HY 2007 The story of Rett syndrome: from clinic to neurobiology. Neuron 56 422–437. (https://doi.org/10.1016/j.neuron.2007.10.001)
Chang YP, Ka SM, Hsu WH, Chen A, Chao LK, Lin CC, Hsieh CC, Chen MC, Chiu HW & Ho CL et al.2015 Resveratrol inhibits NLRP3 inflammasome activation by preserving mitochondrial integrity and augmenting autophagy. Journal of Cellular Physiology 230 1567–1579. (https://doi.org/10.1002/jcp.24903)
Chen HH, Chang PC, Chen C & Chan MH 2018 Protective and therapeutic activity of honokiol in reversing motor deficits and neuronal degeneration in the mouse model of Parkinson’s disease. Pharmacological Reports 70 668–676. (https://doi.org/10.1016/j.pharep.2018.01.003)
Cheng Y, Takeuchi H, Sonobe Y, Jin S, Wang Y, Horiuchi H, Parajuli B, Kawanokuchi J, Mizuno T & Suzumura A 2014 Sirtuin 1 attenuates oxidative stress via upregulation of superoxide dismutase 2 and catalase in astrocytes. Journal of Neuroimmunology 269 38–43. (https://doi.org/10.1016/j.jneuroim.2014.02.001)
Christodoulou J, Grimm A, Maher T & Bennetts B 2003 RettBASE: the IRSA MECP2 variation database – a new mutation database in evolution. Human Mutation 21 466–472. (https://doi.org/10.1002/humu.10194)
Chun P 2015 Role of sirtuins in chronic obstructive pulmonary disease. Archives of Pharmacal Research 38 1–10. (https://doi.org/10.1007/s12272-014-0494-2)
Cordone V, Ferrara F, Pecorelli A, Guiotto A, Vitale A, Amicarelli F, Cervellati C, Hayek J & Valacchi G 2022 The constitutive activation of TLR4-IRAK1-NFκB axis is involved in the early NLRP3 inflammasome response in peripheral blood mononuclear cells of Rett syndrome patients. Free Radical Biology and Medicine 181 1–13. (https://doi.org/10.1016/j.freeradbiomed.2022.01.017)
Cortelazzo A, De Felice C, Guerranti R, Signorini C, Leoncini S, Pecorelli A, Zollo G, Landi C, Valacchi G & Ciccoli L et al.2014 Subclinical inflammatory status in Rett syndrome. Mediators of Inflammation 2014 480980. (https://doi.org/10.1155/2014/480980)
Cortelazzo A, De Felice C, Guy J, Timperio AM, Zolla L, Guerranti R, Leoncini S, Signorini C, Durand T & Hayek J 2020 Brain protein changes in Mecp2 mouse mutant models: effects on disease progression of Mecp2 brain specific gene reactivation. Journal of Proteomics 210 103537. (https://doi.org/10.1016/j.jprot.2019.103537)
Cronk JC, Derecki NC, Ji E, Xu Y, Lampano AE, Smirnov I, Baker W, Norris GT, Marin I & Coddington N et al.2015 Methyl-CpG binding protein 2 regulates microglia and macrophage gene expression in response to inflammatory stimuli. Immunity 42 679–691. (https://doi.org/10.1016/j.immuni.2015.03.013)
Cuddapah VA, Pillai RB, Shekar KV, Lane JB, Motil KJ, Skinner SA, Tarquinio DC, Glaze DG, McGwin G & Kaufmann WE et al.2014 Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. Journal of Medical Genetics 51 152–158. (https://doi.org/10.1136/jmedgenet-2013-102113)
De Felice C, Ciccoli L, Leoncini S, Signorini C, Rossi M, Vannuccini L, Guazzi G, Latini G, Comporti M & Valacchi G et al.2009 Systemic oxidative stress in classic Rett syndrome. Free Radical Biology and Medicine 47 440–448. (https://doi.org/10.1016/j.freeradbiomed.2009.05.016)
De Felice C, Signorini C, Durand T, Oger C, Guy A, Bultel-Poncé V, Galano JM, Ciccoli L, Leoncini S & D’Esposito M et al.2011 F2-dihomo-isoprostanes as potential early biomarkers of lipid oxidative damage in Rett syndrome. Journal of Lipid Research 52 2287–2297. (https://doi.org/10.1194/jlr.P017798)
De Felice C, Della Ragione F, Signorini C, Leoncini S, Pecorelli A, Ciccoli L, Scalabrì F, Marracino F, Madonna M & Belmonte G et al.2014 Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. Neurobiology of Disease 68 66–77. (https://doi.org/10.1016/j.nbd.2014.04.006)
De Sá Coutinho D, Pacheco MT, Frozza RL & Bernardi A 2018 Anti-inflammatory effects of resveratrol: mechanistic insights. International Journal of Molecular Sciences 19 1812. (https://doi.org/10.3390/ijms19061812)
Di Emidio G, Falone S, Artini PG, Amicarelli F, D’Alessandro AM & Tatone C 2021 Mitochondrial sirtuins in reproduction. Antioxidants 10 1047. (https://doi.org/10.3390/antiox10071047)
Du S & Zheng H 2021 Role of FoxO transcription factors in aging and age-related metabolic and neurodegenerative diseases. Cell and Bioscience 11 188. (https://doi.org/10.1186/s13578-021-00700-7)
Ehrhart F, Jacobsen A, Rigau M, Bosio M, Kaliyaperumal R, Laros JFJ, Willighagen EL, Valencia A, Roos M & Capella-Gutierrez S et al.2021 A catalogue of 863 Rett-syndrome-causing MECP2 mutations and lessons learned from data integration. Scientific Data 8 10. (https://doi.org/10.1038/s41597-020-00794-7)
Feldman JL, Baeza J & Denu JM 2013 Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. Journal of Biological Chemistry 288 31350–31356. (https://doi.org/10.1074/jbc.C113.511261)
Fernando KKM & Wijayasinghe YS 2021 Sirtuins as potential therapeutic targets for mitigating neuroinflammation associated with Alzheimer’s disease. Frontiers in Cellular Neuroscience 15 746631. (https://doi.org/10.3389/fncel.2021.746631)
Filosa S, Pecorelli A, D’Esposito M, Valacchi G & Hajek J 2015 Exploring the possible link between MeCP2 and oxidative stress in Rett syndrome. Free Radical Biology and Medicine 88 81–90. (https://doi.org/10.1016/j.freeradbiomed.2015.04.019)
Finley LWS, Haas W, Desquiret-Dumas V, Wallace DC, Procaccio V, Gygi SP & Haigis MC 2011 Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS ONE 6 e23295. (https://doi.org/10.1371/journal.pone.0023295)
Gerdts J, Brace EJ, Sasaki Y, DiAntonio A & Milbrandt J 2015 SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science 348 453–457. (https://doi.org/10.1126/science.1258366)
Gibellini L, Pinti M, Beretti F, Pierri CL, Onofrio A, Riccio M, Carnevale G, De Biasi S, Nasi M & Torelli F et al.2014 Sirtuin 3 interacts with Lon protease and regulates its acetylation status. Mitochondrion 18 76–81. (https://doi.org/10.1016/j.mito.2014.08.001)
Gold WA, Lacina TA, Cantrill LC & Christodoulou J 2015 MeCP2 deficiency is associated with reduced levels of tubulin acetylation and can be restored using HDAC6 inhibitors. Journal of Molecular Medicine 93 63–72. (https://doi.org/10.1007/s00109-014-1202-x)
Gold WA, Krishnarajy R, Ellaway C & Christodoulou J 2018 Rett syndrome: a genetic update and clinical review focusing on comorbidities. ACS Chemical Neuroscience 9 167–176. (https://doi.org/10.1021/acschemneuro.7b00346)
Gomes BAQ, Silva JPB, Romeiro CFR, dos Santos SM, Rodrigues CA, Gonçalves PR, Sakai JT, Mendes PFS, Varela ELP & Monteiro MC 2018 Neuroprotective mechanisms of resveratrol in Alzheimer’s disease: role of SIRT1. Oxidative Medicine and Cellular Longevity 2018 8152373. (https://doi.org/10.1155/2018/8152373)
Guo P, Pi H, Xu S, Zhang L, Li Y, Li M, Cao Z, Tian L, Xie J & Li R et al.2014 Melatonin improves mitochondrial function by promoting MT1/SIRT1/PGC-1 alpha-dependent mitochondrial biogenesis in cadmium-induced hepatotoxicity in vitro. Toxicological Sciences 142 182–195. (https://doi.org/10.1093/toxsci/kfu164)
Gurd BJ 2011 Deacetylation of PGC-1α by SIRT1: importance for skeletal muscle function and exercise-induced mitochondrial biogenesis. Applied Physiology, Nutrition, and Metabolism 36 589–597. (https://doi.org/10.1139/h11-070)
Han Y, Sun W, Ren D, Zhang J, He Z, Fedorova J, Sun X, Han F & Li J 2020 SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion. Redox Biology 34 101538. (https://doi.org/10.1016/j.redox.2020.101538)
He Q, Li Z, Wang Y, Hou Y, Li L & Zhao J 2017 Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction. International Immunopharmacology 50 208–215. (https://doi.org/10.1016/j.intimp.2017.06.029)
He M, Chiang HH, Luo H, Zheng Z, Qiao Q, Wang L, Tan M, Ohkubo R, Mu WC & Zhao S et al.2020 An acetylation switch of the NLRP3 inflammasome regulates aging-associated chronic inflammation and insulin resistance. Cell Metabolism 31 580 .e5–591.e5. (https://doi.org/10.1016/j.cmet.2020.01.009)
Hendouei F, Sanjari Moghaddam H, Mohammadi MR, Taslimi N, Rezaei F & Akhondzadeh S 2020 Resveratrol as adjunctive therapy in treatment of irritability in children with autism: a double-blind and placebo-controlled randomized trial. Journal of Clinical Pharmacy and Therapeutics 45 324–334. (https://doi.org/10.1111/jcpt.13076)
Hou M, Bao W, Gao Y, Chen J & Song G 2022 Honokiol improves cognitive impairment in APP/PS1 mice through activating mitophagy and mitochondrial unfolded protein response. Chemico-Biological Interactions 351 109741. (https://doi.org/10.1016/j.cbi.2021.109741)
Hughes KJ, Meares GP, Hansen PA & Corbett JA 2011 FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide. Journal of Biological Chemistry 286 8338–8348. (https://doi.org/10.1074/jbc.M110.204768)
Imai SI & Guarente L 2016 It takes two to tango: NAD+ and sirtuins in aging/longevity control. NPJ Aging and Mechanisms of Disease 2 16017. (https://doi.org/10.1038/npjamd.2016.17)
Imai S, Armstrong CM, Kaeberlein M & Guarente L 2000 Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403 795–800. (https://doi.org/10.1038/35001622)
Ip JPK, Mellios N & Sur M 2018 Rett syndrome: insights into genetic, molecular and circuit mechanisms. Nature Reviews: Neuroscience 19 368–382. (https://doi.org/10.1038/s41583-018-0006-3)
Jeong H, Dimick MK, Sultan A, Duong A, Park SS, El Soufi El Sabbagh D, Goldstein BI & Andreazza AC 2020 Peripheral biomarkers of mitochondrial dysfunction in adolescents with bipolar disorder. Journal of Psychiatric Research 123 187–193. (https://doi.org/10.1016/j.jpsychires.2020.02.009)
Jiao F & Gong Z 2020 The beneficial roles of SIRT1 in neuroinflammation-related diseases. Oxidative Medicine and Cellular Longevity 2020 6782872. (https://doi.org/10.1155/2020/6782872)
Kauppinen A, Suuronen T, Ojala J, Kaarniranta K & Salminen A 2013 Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cellular Signalling 25 1939–1948. (https://doi.org/10.1016/j.cellsig.2013.06.007)
Kim SY, Cohen BM, Chen X, Lukas SE, Shinn AK, Yuksel AC, Li T, Du F & Öngür D 2017 Redox dysregulation in schizophrenia revealed by in vivo NAD+/NADH measurement. Schizophrenia Bulletin 43 197–204. (https://doi.org/10.1093/schbul/sbw129)
Kishi N, MacDonald JL, Ye J, Molyneaux BJ, Azim E & Macklis JD 2016 Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice. Nature Communications 7 10520. (https://doi.org/10.1038/ncomms10520)
Kitada M, Ogura Y & Koya D 2016 The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis. Aging 8 2290–2307. (https://doi.org/10.18632/aging.101068)
Koo SJ & Garg NJ 2019 Metabolic programming of macrophage functions and pathogens control. Redox Biology 24 101198. (https://doi.org/10.1016/j.redox.2019.101198)
Krafczyk N & Klotz LO 2022 FOXO transcription factors in antioxidant defense. IUBMB Life 74 53–61. (https://doi.org/10.1002/iub.2542)
Kyle SM, Vashi N & Justice MJ 2018 Rett syndrome: a neurological disorder with metabolic components. Open Biology 8 170216. (https://doi.org/10.1098/rsob.170216)
Lee SH, Lee JH, Lee HY & Min KJ 2019 Sirtuin signaling in cellular senescence and aging. BMB Reports 52 24–34. (https://doi.org/10.5483/BMBRep.2019.52.1.290)
Leite JA, Ghirotto B, Targhetta VP, de Lima J & Câmara NOS 2022 Sirtuins as pharmacological targets in neurodegenerative and neuropsychiatric disorders. British Journal of Pharmacology 179 1496–1511. (https://doi.org/10.1111/bph.15570)
Leoncini S, De Felice C, Signorini C, Zollo G, Cortelazzo A, Durand T, Galano JM, Guerranti R, Rossi M & Ciccoli L et al.2015 Cytokine dysregulation in MECP2- and CDKL5-related Rett syndrome: relationships with aberrant redox homeostasis, inflammation, and ω-3 PUFAs. Oxidative Medicine and Cellular Longevity 2015 421624. (https://doi.org/10.1155/2015/421624)
Li H, Khirug S, Cai C, Ludwig A, Blaesse P, Kolikova J, Afzalov R, Coleman SK, Lauri S & Airaksinen MS et al.2007 KCC2 interacts with the dendritic cytoskeleton to promote spine development. Neuron 56 1019–1033. (https://doi.org/10.1016/j.neuron.2007.10.039)
Li H, Jia J, Wang W, Hou T, Tian Y, Wu Q, Xu L, Wei Y & Wang X 2018 Honokiol alleviates cognitive deficits of Alzheimer’s disease (PS1V97L) transgenic mice by activating mitochondrial SIRT3. Journal of Alzheimer’s Disease 64 291–302. (https://doi.org/10.3233/JAD-180126)
Lin ZF, Xu HB, Wang JY, Lin Q, Ruan Z, Liu FB, Jin W, Huang HH & Chen X 2013 SIRT5 desuccinylates and activates SOD1 to eliminate ROS. Biochemical and Biophysical Research Communications 441 191–195. (https://doi.org/10.1016/j.bbrc.2013.10.033)
Liu TF & McCall CE 2013 Deacetylation by SIRT1 reprograms inflammation and cancer. Genes and Cancer 4 135–147. (https://doi.org/10.1177/1947601913476948)
Lutz MI, Milenkovic I, Regelsberger G & Kovacs GG 2014 Distinct patterns of sirtuin expression during progression of Alzheimer’s disease. NeuroMolecular Medicine 16 405–414. (https://doi.org/10.1007/s12017-014-8288-8)
Manjula R, Anuja K & Alcain FJ 2020 SIRT1 and SIRT2 activity control in neurodegenerative diseases. Frontiers in Pharmacology 11 585821. (https://doi.org/10.3389/fphar.2020.585821)
Meng H, Yan WY, Lei YH, Wan Z, Hou YY, Sun LK & Zhou JP 2019 SIRT3 regulation of mitochondrial quality control in neurodegenerative diseases. Frontiers in Aging Neuroscience 11 313. (https://doi.org/10.3389/fnagi.2019.00313)
Mercken EM, Mitchell SJ, Martin-Montalvo A, Minor RK, Almeida M, Gomes AP, Scheibye-Knudsen M, Palacios HH, Licata JJ & Zhang Y et al.2014 SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging Cell 13 787–796. (https://doi.org/10.1111/acel.12220)
Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T & Akira S 2013 Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nature Immunology 14 454–460. (https://doi.org/10.1038/ni.2550)
Misawa T, Saitoh T, Kozaki T, Park S, Takahama M & Akira S 2015 Resveratrol inhibits the acetylated α-tubulin-mediated assembly of the NLRP3-inflammasome. International Immunology 27 425–434. (https://doi.org/10.1093/intimm/dxv018)
Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS & Turner RS 2017 Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. Journal of Neuroinflammation 14 1. (https://doi.org/10.1186/s12974-016-0779-0)
Nakagawa T & Guarente L 2011 Sirtuins at a glance. Journal of Cell Science 124 833–838. (https://doi.org/10.1242/jcs.081067)
Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, Leonard H, Bailey MES, Schanen NC & Zappella M et al.2010 Rett syndrome: revised diagnostic criteria and nomenclature. Annals of Neurology 68 944–950. (https://doi.org/10.1002/ana.22124)
Pan W, Yu H, Huang S & Zhu P 2016 Resveratrol protects against TNF-α-induced injury in human umbilical endothelial cells through promoting Sirtuin-1-induced repression of NF-kB and p38 MAPK. PLoS ONE 11 e0147034. (https://doi.org/10.1371/journal.pone.0147034)
Pardo PS & Boriek AM 2020 SIRT1 regulation in ageing and obesity. Mechanisms of Ageing and Development 188 111249. (https://doi.org/10.1016/j.mad.2020.111249)
Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP & Brown K 2011 Clinical trials of resveratrol. Annals of the New York Academy of Sciences 1215 161–169. (https://doi.org/10.1111/j.1749-6632.2010.05853.x)
Pecorelli A, Ciccoli L, Signorini C, Leoncini S, Giardini A, D’Esposito M, Filosa S, Hayek J, De Felice C & Valacchi G 2011 Increased levels of 4HNE-protein plasma adducts in Rett syndrome. Clinical Biochemistry 44 368–371. (https://doi.org/10.1016/j.clinbiochem.2011.01.007)
Pecorelli A, Cervellati C, Cordone V, Amicarelli F, Hayek J & Valacchi G 2019 13-HODE, 9-HODE and ALOX15 as potential players in Rett syndrome OxInflammation. Free Radical Biology and Medicine 134 598–603. (https://doi.org/10.1016/j.freeradbiomed.2019.02.007)
Pecorelli A, Cervellati C, Cordone V, Hayek J & Valacchi G 2020a Compromised immune/inflammatory responses in Rett syndrome. Free Radical Biology and Medicine 152 100–106. (https://doi.org/10.1016/j.freeradbiomed.2020.02.023)
Pecorelli A, Cordone V, Messano N, Zhang C, Falone S, Amicarelli F, Hayek J & Valacchi G 2020b Altered inflammasome machinery as a key player in the perpetuation of Rett syndrome oxinflammation. Redox Biology 28 101334. (https://doi.org/10.1016/j.redox.2019.101334)
Pecorelli A, Cervellati C, Hayek J & Valacchi G 2016a OxInflammation in Rett syndrome. International Journal of Biochemistry and Cell Biology 81 246–253. (https://doi.org/10.1016/j.biocel.2016.07.015)
Pecorelli A, Cervellati F, Belmonte G, Montagner G, Waldon P, Hayek J, Gambari R & Valacchi G 2016b Cytokines profile and peripheral blood mononuclear cells morphology in Rett and autistic patients. Cytokine 77 180–188. (https://doi.org/10.1016/j.cyto.2015.10.002)
Rahman S & Islam R 2011 Mammalian Sirt1: insights on its biological functions. Cell Communication and Signaling 9 11. (https://doi.org/10.1186/1478-811X-9-11)
Rahman I, Kinnula VL, Gorbunova V & Yao H 2012 SIRT1 as a therapeutic target in inflammaging of the pulmonary disease. Preventive Medicine 54 (Supplement) S20–S28. (https://doi.org/10.1016/j.ypmed.2011.11.014)
Rahman M, Nirala NK, Singh A, Zhu LJ, Taguchi K, Bamba T, Fukusaki E, Shaw LM, Lambright DG & Acharya JK et al.2014 Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity. Journal of Cell Biology 206 289–305. (https://doi.org/10.1083/jcb.201404118)
Rett A 1966 On a unusual brain atrophy syndrome in hyperammonemia in childhood. Wiener Medizinische Wochenschrift 116 723–726.
Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM & Puigserver P 2005 Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434 113–118. (https://doi.org/10.1038/nature03354)
Salminen A, Kaarniranta K & Kauppinen A 2013 Crosstalk between oxidative stress and SIRT1: impact on the aging process. International Journal of Molecular Sciences 14 3834–3859. (https://doi.org/10.3390/ijms14023834)
Segatto M, Trapani L, Di Tunno I, Sticozzi C, Valacchi G, Hayek J & Pallottini V 2014 Cholesterol metabolism is altered in Rett syndrome: a study on plasma and primary cultured fibroblasts derived from patients. PLoS ONE 9 e104834. (https://doi.org/10.1371/journal.pone.0104834)
Sferra A, Nicita F & Bertini E 2020 Microtubule dysfunction: a common feature of neurodegenerative diseases. International Journal of Molecular Sciences 21 7354. (https://doi.org/10.3390/ijms21197354)
Shaheen MJ, Bekdash AM, Itani HA & Borjac JM 2021 Saffron extract attenuates neuroinflammation in rmTBI mouse model by suppressing NLRP3 inflammasome activation via SIRT1. PLoS ONE 16 e0257211. (https://doi.org/10.1371/journal.pone.0257211)
Shulyakova N, Andreazza AC, Mills LR & Eubanks JH 2017 Mitochondrial dysfunction in the pathogenesis of Rett syndrome: implications for mitochondria-targeted therapies. Frontiers in Cellular Neuroscience 11 58. (https://doi.org/10.3389/fncel.2017.00058)
Signorini C, Leoncini S, De Felice C, Pecorelli A, Meloni I, Ariani F, Mari F, Amabile S, Paccagnini E & Gentile M et al.2014 Redox imbalance and morphological changes in skin fibroblasts in typical Rett syndrome. Oxidative Medicine and Cellular Longevity 2014 195935. (https://doi.org/10.1155/2014/195935)
Singh CK, Chhabra G, Ndiaye MA, Garcia-Peterson LM, Mack NJ & Ahmad N 2018 The role of sirtuins in antioxidant and redox signaling. Antioxidants and Redox Signaling 28 643–661. (https://doi.org/10.1089/ars.2017.7290)
Smedler E, Kleppe J, Neufeld J, Lundin K, Bölte S & Landén M 2021 Cerebrospinal fluid and serum protein markers in autism: a co-twin study. Journal of Neurochemistry 158 798–806. (https://doi.org/10.1111/jnc.15338)
Sticozzi C, Belmonte G, Pecorelli A, Cervellati F, Leoncini S, Signorini C, Ciccoli L, De Felice C, Hayek J & Valacchi G 2013 Scavenger receptor B1 post-translational modifications in Rett syndrome. FEBS Letters 587 2199–2204. (https://doi.org/10.1016/j.febslet.2013.05.042)
Tang X, Kim J, Zhou L, Wengert E, Zhang L, Wu Z, Carromeu C, Muotri AR, Marchetto MCN & Gage FH et al.2016 KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. PNAS 113 751–756. (https://doi.org/10.1073/pnas.1524013113)
Tang X, Drotar J, Li K, Clairmont CD, Brumm AS, Sullins AJ, Wu H, Liu XS, Wang J & Gray NS et al.2019 Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice. Science Translational Medicine 11 eaau0164. (https://doi.org/10.1126/scitranslmed.aau0164)
Tang X, Zhao Y, Zhou Z, Yan J, Zhou B, Chi X, Luo A & Li S 2020 Resveratrol mitigates sevoflurane-induced neurotoxicity by the SIRT1-dependent regulation of BDNF expression in developing mice. Oxidative Medicine and Cellular Longevity 2020 9018624. (https://doi.org/10.1155/2020/9018624)
Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S & Hayes McDonald W et al.2010 Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Molecular Cell 40 893–904. (https://doi.org/10.1016/j.molcel.2010.12.013)
Traba J & Sack MN 2017 The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome. Cellular and Molecular Life Sciences 74 1777–1791. (https://doi.org/10.1007/s00018-016-2431-7)
Tsujimura K, Irie K, Nakashima H, Egashira Y, Fukao Y, Fujiwara M, Itoh M, Uesaka M, Imamura T & Nakahata Y et al.2015 miR-199a links MeCP2 with mTOR signaling and its dysregulation leads to Rett syndrome phenotypes. Cell Reports 12 1887–1901. (https://doi.org/10.1016/j.celrep.2015.08.028)
Tyagi A, Nguyen CU, Chong T, Michel CR, Fritz KS, Reisdorph N, Knaub L, Reusch JEB & Pugazhenthi S 2018 SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain. Scientific Reports 8 17547. (https://doi.org/10.1038/s41598-018-35890-7)
Vachharajani VT, Liu T, Wang X, Hoth JJ, Yoza BK & McCall CE 2016 Sirtuins link inflammation and metabolism. Journal of Immunology Research 2016 8167273. (https://doi.org/10.1155/2016/8167273)
Valacchi G, Virgili F, Cervellati C & Pecorelli A 2018 OxInflammation: from subclinical condition to pathological biomarker. Frontiers in Physiology 9 858. (https://doi.org/10.3389/fphys.2018.00858)
van de Ven RAH, Santos D & Haigis MC 2017 Mitochondrial sirtuins and molecular mechanisms of aging. Trends in Molecular Medicine 23 320–331. (https://doi.org/10.1016/j.molmed.2017.02.005)
Ventura-Clapier R, Garnier A & Veksler V 2008 Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovascular Research 79 208–217. (https://doi.org/10.1093/cvr/cvn098)
Wang F, Nguyen M, Qin FX-F & Tong Q 2007 SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell 6 505–514. (https://doi.org/10.1111/j.1474-9726.2007.00304.x)
Wang X, Hu S & Liu L 2017 Phosphorylation and acetylation modifications of FOXO3a: independently or synergistically? Oncology Letters 13 2867–2872. (https://doi.org/10.3892/ol.2017.5851)
Wang J, Xiao Y, Liu C, Huang Y, Petersen RB, Zheng L & Huang K 2021 Emerging physiological and pathological roles of MeCP2 in non-neurological systems. Archives of Biochemistry and Biophysics 700 108768. (https://doi.org/10.1016/j.abb.2021.108768)
Wu YT, Lee HC, Liao CC & Wei YH 2013 Regulation of mitochondrial F(o)F(1)ATPase activity by Sirt3-catalyzed deacetylation and its deficiency in human cells harboring 4977 bp deletion of mitochondrial DNA. Biochimica et Biophysica Acta 1832 216–227. (https://doi.org/10.1016/j.bbadis.2012.10.002)
Xia DY, Yuan JL, Jiang XC, Qi M, Lai NS, Wu LY & Zhang XS 2021 SIRT1 promotes M2 microglia polarization via reducing ROS-mediated NLRP3 inflammasome signaling after subarachnoid hemorrhage. Frontiers in Immunology 12 770744. (https://doi.org/10.3389/fimmu.2021.770744)
Xiong S, Salazar G, Patrushev N & Alexander RW 2011 FoxO1 mediates an autofeedback loop regulating SIRT1 expression. Journal of Biological Chemistry 286 5289–5299. (https://doi.org/10.1074/jbc.M110.163667)
Ye J, Liu Z, Wei J, Lu L, Huang Y, Luo L & Xie H 2013 Protective effect of SIRT1 on toxicity of microglial-derived factors induced by LPS to PC12 cells via the p53-caspase-3-dependent apoptotic pathway. Neuroscience Letters 553 72–77. (https://doi.org/10.1016/j.neulet.2013.08.020)
Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA & Mayo MW 2004 Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO Journal 23 2369–2380. (https://doi.org/10.1038/sj.emboj.7600244)
Yin J, Han P, Song M, Nielsen M, Beach TG, Serrano GE, Liang WS, Caselli RJ & Shi J 2018 Amyloid-β increases Tau by mediating sirtuin 3 in Alzheimer’s disease. Molecular Neurobiology 55 8592–8601. (https://doi.org/10.1007/s12035-018-0977-0)
Zarzuelo MJ, López-Sepúlveda R, Sánchez M, Romero M, Gómez-Guzmán M, Ungvary Z, Pérez-Vizcaíno F, Jiménez R & Duarte J 2013 SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: implications for vascular aging. Biochemical Pharmacology 85 1288–1296. (https://doi.org/10.1016/j.bcp.2013.02.015)
Zhao K, Harshaw R, Chai X & Marmorstein R 2004 Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases. PNAS 101 8563–8568. (https://doi.org/10.1073/pnas.0401057101)
Zhao D, Mokhtari R, Pedrosa E, Birnbaum R, Zheng D & Lachman HM 2017 Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress. Molecular Autism 8 17. (https://doi.org/10.1186/s13229-017-0134-z)
Zheng R, Ruan Y, Yan Y, Lin Z, Xue N, Yan Y, Tian J, Yin X, Pu J & Zhang B 2021 Melatonin attenuates neuroinflammation by down-regulating NLRP3 inflammasome via a SIRT1-dependent pathway in MPTP-induced models of Parkinson’s disease. Journal of Inflammation Research 14 3063–3075. (https://doi.org/10.2147/JIR.S317672)
Zhou Y, Wang S, Li Y, Yu S & Zhao Y 2017 SIRT1/PGC-1α signaling promotes mitochondrial functional recovery and reduces apoptosis after intracerebral hemorrhage in rats. Frontiers in Molecular Neuroscience 10 443. (https://doi.org/10.3389/fnmol.2017.00443)
Zhu W, Chen S, Li Z, Zhao X, Li W, Sun Y, Zhang Z, Ling W & Feng X 2014 Effects and mechanisms of resveratrol on the amelioration of oxidative stress and hepatic steatosis in KKAy mice. Nutrition and Metabolism 11 35. (https://doi.org/10.1186/1743-7075-11-35)
Zocchi L & Sassone-Corsi P 2012 SIRT1-mediated deacetylation of MeCP2 contributes to BDNF expression. Epigenetics 7 695–700. (https://doi.org/10.4161/epi.20733)
Zou P, Liu X, Li G & Wang Y 2018 Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1. Molecular Medicine Reports 17 3212–3217. (https://doi.org/10.3892/mmr.2017.8241)
