Targeted attenuation of elevated histone marks at
            <i>SNCA</i>
            alleviates α‐synuclein in Parkinson's disease

Guhathakurta, Subhrangshu; Kim, Jin-Il; Adams, Levi; Basu, Sambuddha; Kyung, Song Min; Adler, Evan; Je, Goun; Fiadeiro, Mariana Bernardo; Kim, Yoon Seong

doi:10.15252/emmm.202012188

Cited by 59 publications

(47 citation statements)

References 64 publications

(87 reference statements)

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“…Guhathakurta and colleagues found the transcription promoting mark H3K4me3 signi cantly enriched at the SNCA promotor and intron1 region of substantia nigra in post-mortem PD brain samples. Furthermore, directed de-methylation of H3K4me3 at the SNCA promotor decreased SNCA mRNA and protein levels in SH-SY5Y cells and idiopathic PD-iPSC [ 15 ].…”

Section: Discussionmentioning

confidence: 93%

Activators of Alpha Synuclein Expression Identified by Reporter Cell Line-based High Throughput Drug Screen

Stahl

Denner

Piston

et al. 2021

Preprint

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Multiplications, mutations and dysregulation of the alpha synuclein gene (SNCA) are associated with the demise of dopaminergic neurons and are considered to play important roles in the pathogenesis of familial and sporadic forms of Parkinson’s disease. Regulation of SNCA expression might thus be an appropriate target for treatment. We aimed to identify specific modulators of SNCA transcription, generated CRISPR/Cas9 modified SNCA-GFP-luciferase (LUC) genomic fusion- and control cell lines and screened a library of 1649 bioactive compounds, including the FDA approved drugs. We found no inhibitors but three selective activators which increased SNCA mRNA and protein levels.

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Section: Discussionmentioning

confidence: 93%

Activators of Alpha Synuclein Expression Identified by Reporter Cell Line-based High Throughput Drug Screen

Stahl

Denner

Piston

et al. 2021

Preprint

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“…Interestingly, overexpression of α-SYN in flies and neuronal cells, such as SH-SY5Y enhanced G9a, H3K9me1, and H3K9me2 levels and H3K9me2-target genes (L1cam, Snap25) eventually lead to impaired synaptic activity [ 144 ]. In contrast, H3K4me3 was significantly enriched at the SNCA promoter region in postmortem brain samples from patients with PD and matched controls [ 145 ]. Similarly, using dead Cas9-Suntag system-mediated locus-specific approaches, the reduction in H3K4me3 from the SNCA promoter reduced α-synuclein levels in neuronal cell lines and PD-derived induced pluripotent stem cell lines (iPSCs) [ 145 ].…”

Section: Parkinson’s Disease (Pd)mentioning

confidence: 99%

“…In contrast, H3K4me3 was significantly enriched at the SNCA promoter region in postmortem brain samples from patients with PD and matched controls [ 145 ]. Similarly, using dead Cas9-Suntag system-mediated locus-specific approaches, the reduction in H3K4me3 from the SNCA promoter reduced α-synuclein levels in neuronal cell lines and PD-derived induced pluripotent stem cell lines (iPSCs) [ 145 ]. Significant H3K4me3 enrichment was observed at the SNCA promoter in the neuronal nuclei (NeuN) of positive neurons of substantia nigra (SN) tissue samples from PD patients.…”

Section: Parkinson’s Disease (Pd)mentioning

confidence: 99%

“…In the same model, pretreatment with GSK-J4, a potent inhibitor of KDM6A/B and KDM5B/C (demethylates H3K27me3/me2 and H3K4me3/me2 respectively) [ 147 , 148 ], significantly prevented H3K4me3 and H3K27me3 marks’ decrease [ 146 ]. In contrast to the cell culture model, increased H3K27me3 levels were found in PD patients’ brains [ 145 ], indicating the possible role of PRC2 in vivo PD models. These findings indicate that abnormal histone methylation, such as H3K4me3 (gene activation) and H3K27me3 (gene suppression), control gene expression (e.g., α-synuclein) in SN neurons from patients with PD.…”

Section: Parkinson’s Disease (Pd)mentioning

confidence: 99%

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Histone Methylation Regulation in Neurodegenerative Disorders

Basavarajappa

Subbanna

2021

IJMS

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Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttranslational modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation-mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disorders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific pathological factors. We have discussed the current state of histone methylation, therapeutic strategies, and future perspectives for these disorders. While not somatically heritable, the enzymes responsible for histone methylation regulation, such as histone methyltransferases and demethylases in neurons, are dynamic and reversible. They have become promising potential therapeutic targets to treat or prevent several neurodegenerative disorders. These findings, along with clinical data, may provide links between molecular-level changes and behavioral differences and provide novel avenues through which the epigenome may be targeted early on in people at risk for neurodegenerative disorders.

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“…Moreover, this ‘ disease in a dish’ modeling system can facilitate both high throughput drug discovery and research into cellular therapy approaches. Future work with CRISPR-Cas9 technology in combination with iPSCs may revolutionize the approach to synucleinopathies with the aim of replacing the deleterious mutations or deleting the multiplications from the key disease genes [ 83 ] or indeed modulation of related mechanisms such as histones involved in post-translational modifications [ 84 ].…”

Section: Future Directions With Ipsc Models Of α-Synuclein Pathologymentioning

confidence: 99%

α-synuclein pathogenesis in hiPSC models of Parkinson’s disease

2021

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α-synuclein is an increasingly prominent player in the pathology of a variety of neurodegenerative conditions. Parkinson’s disease (PD) is a neurodegenerative disorder that affects mainly the dopaminergic neurons in the substantia nigra of the brain. Typical of PD pathology is the finding of protein aggregations termed ‘Lewy bodies’ in the brain regions affected. α-synuclein is implicated in many disease states including dementia with Lewy bodies and Alzheimer’s disease. However, PD is the most common synucleinopathy and continues to be a significant focus of PD research in terms of the α-synuclein Lewy body pathology. Mutations in several genes are associated with PD development including SNCA, which encodes α-synuclein. A variety of model systems have been employed to study α-synuclein physiology and pathophysiology in an attempt to relate more closely to PD pathology. These models include cellular and animal system exploring transgenic technologies, viral vector expression and knockdown approaches, and models to study the potential prion protein-like effects of α-synuclein. The current review focuses on human induced pluripotent stem cell (iPSC) models with a specific focus on mutations or multiplications of the SNCA gene. iPSCs are a rapidly evolving technology with huge promise in the study of normal physiology and disease modeling in vitro. The ability to maintain a patient's genetic background and replicate similar cell phenotypes make iPSCs a powerful tool in the study of neurological diseases. This review focus on the current knowledge about α-synuclein physiological function as well as its role in PD pathogenesis based on human iPSC models.

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Targeted attenuation of elevated histone marks at SNCA alleviates α‐synuclein in Parkinson's disease

Cited by 59 publications

References 64 publications

Activators of Alpha Synuclein Expression Identified by Reporter Cell Line-based High Throughput Drug Screen

Activators of Alpha Synuclein Expression Identified by Reporter Cell Line-based High Throughput Drug Screen

Histone Methylation Regulation in Neurodegenerative Disorders

α-synuclein pathogenesis in hiPSC models of Parkinson’s disease

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