This Norwegian group has found that idiopathic PD patients (with mitochondrial energy production dysfunction) have a so-called histone acetylation problem. Histone acetylation is a fundamental mechanism modulating gene expression. As we know only 5-10 % of PD cases have a genetic background. Now this paper tells that the cause of PD is not genes themselves but perhaps the epigenetic factors which can influence which genes get active. Histone acetylation can be influenced or modulated by drugs, hopefully also by ATH434 one day. If iron overload is the most important or very important epigenetic factor causing PD needs to be seen, but at least the animal studies support iron to have a big role, and sure it is an epigenetic factor at the mitochondrion level.
Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson's disease brain
AffiliationsPMCID: PMC8097820 DOI: 10.1186/s13024-021-00450-7Free PMC article
- PMID: 33947435
Abstract
Background: Parkinson's disease (PD) is a complex, age-related neurodegenerative disorder of largely unknown etiology. PD is strongly associated with mitochondrial respiratory dysfunction, which can lead to epigenetic dysregulation and specifically altered histone acetylation. Nevertheless, and despite the emerging role of epigenetics in age-related brain disorders, the question of whether aberrant histone acetylation is involved in PD remains unresolved.
Methods: We studied fresh-frozen brain tissue from two independent cohorts of individuals with idiopathic PD (n = 28) and neurologically healthy controls (n = 21). We performed comprehensive immunoblotting to identify histone sites with altered acetylation levels in PD, followed by chromatin immunoprecipitation sequencing (ChIP-seq). RNA sequencing data from the same individuals was used to assess the impact of altered histone acetylation on gene expression.
Results: Immunoblotting analyses revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. ChIP-seq analysis further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon with a strong predilection for genes implicated in the disease, including SNCA, PARK7, PRKN and MAPT. Integration of the ChIP-seq with transcriptomic data from the same individuals revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Strikingly, this decoupling was most pronounced among nuclear-encoded mitochondrial genes, corroborating the notion that impaired crosstalk between the nucleus and mitochondria is involved in the pathogenesis of PD. Our findings independently replicated in the two cohorts.
Conclusions: Our findings strongly suggest that aberrant histone acetylation and altered transcriptional regulation are involved in the pathophysiology of PD. We demonstrate that PD-associated genes are particularly prone to epigenetic dysregulation and identify novel epigenetic signatures associated with the disease.
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