PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death

Choi, Hyo‐Kyoung; Choi, Yun‐Sang; Kang, Hee-Bum; Lim, Eunhee; Park, Soo Yeon; Lee, Hyun‐Seob; Park, Ji-Min; Moon, Jisook; Kim, Yun Joong; Choi, Insup; Joe, Eun‐Hye; Choi, Kyung‐Chul; Yoon, Ho‐Geun

doi:10.1093/hmg/ddu526

Cited by 39 publications

(32 citation statements)

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“…However, the molecular events that initiate the shuttling after stroke are not clear. HDAC3 was reported to participate in dopaminergic neuronal cell death 29 and embryonic neurogenesis. 24 Over the past few years, pharmacological manipulations with nonspecific HDAC inhibitors have shown severe dose-limiting toxicities when translated to clinical trials.…”

Section: Discussionmentioning

confidence: 99%

The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome

et al. 2019

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contributed equally to the research work.Abbreviations: AIM2, absent in melanoma 2; ASC, apoptosis speck-like protein; BBB, brain-blood barrier; DAMPs, damaged-associated molecular patterns; ECA, external carotid artery; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic protein; HDAC3, histone deacetylases 3; Iba-1, ionized calcium binding adaptor molecule 1; LPS, lipopolysaccharide; MCAO, middle cerebral artery occlusion; NeuN, neuronal nuclei; Nrf2, nuclear factor E2-related factor-2; PYD, N-terminal pyrin domain; TTC, 2,3,5-triphenyltetrazolium chloride AbstractHistone deacetylases 3 (HDAC3) modulates the acetylation state of histone and nonhistone proteins and could be a powerful regulator of the inflammatory process in stroke. Inflammasome activation is a ubiquitous but poorly understood consequence of acute ischemic stroke. Here, we investigated the potential contributions of HDAC3 to inflammasome activation in primary cultured microglia and experimental stroke models. In this study, we documented that HDAC3 expression was increased in microglia of mouse experimental stroke model. Intraperitoneal injection of RGFP966 (a selective inhibitor of HDAC3) decreased infarct size and alleviated neurological deficits after the onset of middle cerebral artery occlusion (MCAO). In vitro data indicated that LPS stimulation evoked a time-dependent increase of HDAC3 and absent in melanoma 2 (AIM2) inflammasome in primary cultured microglia.Interestingly, AIM2 was subjected to spatiotemporal regulation by RGFP966. The ability of RGFP966 to inhibit the AIM2 inflammasome was confirmed in an experimental mouse model of stroke. As expected, AIM2 knockout mice also demonstrated significant resistance to ischemia injury compared with their wild-type littermates. RGFP966 failed to exhibit extra protective effects in AIM2−/− stroke mice. Furthermore, we found that RGFP966 enhanced STAT1 acetylation and subsequently attenuated STAT1 phosphorylation, which may at least partially contributed to the negative regulation of AIM2 by RGFP966. Together, we initially found that RGFP966 alleviated the inflammatory response and protected against ischemic stroke by regulating the AIM2 inflammasome. K E Y W O R D SAIM2 inflammasome, HDAC3, microglia, STAT1, stroke | 649 ZHANG et Al.

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Section: Discussionmentioning

confidence: 99%

The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome

et al. 2019

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“…For example, the activity of HDAC1, 4, 5 or 6 contributes to neuronal apoptosis, 43, 44, 45, 46, 47 whereas HDAC2, 3, 7 or Sirt1 are known to promote neuronal survival. 9, 38, 48, 49, 50 The current evidence cannot completely explain the antiapoptotic effects of HDACIs in neurons because a global inhibition of HDACs by the pan-HDACIs would result in compromised effects between pro-survival HDAC signals and pro-apoptotic ones. Therefore, the critical event of acetylation loss-coupled neuronal apoptosis needs further exploration.…”

Section: Discussionmentioning

confidence: 91%

“…29, 38 We then asked whether the loss of GCN5 activity is involved in potassium deprivation- or glutamate-induced Bim upregulation and apoptosis. Greatly,CGNs treated with 25K or 5K for 4 h or glutamate (in 25K) for 8 h caused a dramatic reduction in the acetylation of H3K9, meaning that GCN5 activity decreases (Figures 6a and 1a).…”

Section: Resultsmentioning

confidence: 99%

Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim

Xia

et al. 2017

Cell Death Dis

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Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons. Mechanistically, the BH3-only protein Bim is transcriptionally upregulated by activated Egr-1 and E2F1 and mediates apoptosis following GCN5 inhibition. Furthermore, in the activity withdrawal- or glutamate-evoked neuronal apoptosis models, GCN5 loses its activity, in contrast to Bim induction. Adenovirus-mediated overexpression of GCN5 suppresses Bim induction and apoptosis. Interestingly, the loss of GCN5 activity and the induction of Egr-1, E2F1 and Bim are involved in the early brain injury (EBI) following subarachnoid haemorrhage (SAH) in rats. HDAC inhibition not only significantly rescues Bim expression and apoptosis induced by either potassium deprivation or GCN5 inactivation but also ameliorates these events and EBI in SAH rats. Taken together, our results highlight a new mechanism by which the loss of GCN5 activity promotes neuronal apoptosis through the transcriptional upregulation of Bim, which is probably a critical event in triggering neuronal death when cellular acetylation homeostasis is impaired.

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“…MAPT haplotype H1 is preferentially associated with H3K4me3 histone modification, which normally indicates gene activation, whereas the H2 haplotype is associated with the repressive H3K27me3 histone modification [94]. The PINK1 protein can bind to HDAC3, a transcriptional repressor recruited to specific promoters, and upregulate its histone deacetylase activity through phosphorylation in neuronal cell lines [14]. This event leads to increased binding of phosphorylated HDAC3 to p53, which decreases p53 acetylation and stability, thus inhibiting p53-mediated neuronal apoptosis.…”

Section: Chromatin Remodelingmentioning

confidence: 99%

“…This event leads to increased binding of phosphorylated HDAC3 to p53, which decreases p53 acetylation and stability, thus inhibiting p53-mediated neuronal apoptosis. The knockdown of HDAC3 abolishes the effect of PINK1 on p53 [14]. Known PD-associated variants in PINK1 do not promote phosphorylation of HDAC3 suggesting PINK 1 mutations lead to a deregulation of HDAC3 activity and increased susceptibility to p53-dependent neuronal apoptosis and neurodegeneration [14].…”

Section: Chromatin Remodelingmentioning

confidence: 99%

Epigenetic regulation in Parkinson’s disease

2016

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Recent efforts have shed new light on the epigenetic mechanisms driving gene expression alterations associated with Parkinson’s disease (PD) pathogenesis. Changes in gene expression are a well-established cause of PD, and epigenetic mechanisms likely play a pivotal role in regulation. Studies in families with PD harboring duplications and triplications of the SNCA gene have demonstrated that gene dosage is associated with increased expression of both SNCA mRNA and protein, and correlates with a fulminant disease course. Furthermore, it is postulated that even subtle changes in SNCA expression caused by common variation is associated with disease risk. Of note, genome-wide association studies (GWAS) have identified over 30 loci associated with PD with most signals located in non-coding regions of the genome, thus likely influencing transcript expression levels. In health, epigenetic mechanisms tightly regulate gene expression, turning genes on and off to balance homeostasis and this in part explains why two cells with the same DNA sequence will have different RNA expression profiles. Understanding this phenomenon will be crucial to our interpretation of the selective vulnerability observed in neurodegeneration and specifically dopaminergic neurons in the PD brain. In this review, we discuss epigenetic mechanisms, such as DNA methylation and histone modifications, involved in regulating the expression of genes relevant to PD, RNA-based mechanisms, as well as the effect of toxins and potential epigenetic-based treatments for PD.

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PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death

Cited by 39 publications

References 50 publications

The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome

The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome

Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim

Epigenetic regulation in Parkinson’s disease

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