Targeted attenuation of elevated histone marks atSNCAalleviates α-synuclein in Parkinson’s disease

Abstract

Epigenetic de-regulation of α -synuclein plays a key role in Parkinson's disease (PD). Analysis of the SNCA promoter using the ENCODE database revealed the presence of important histone posttranslational modifications (PTMs) including transcription-promoting marks, H3K4me3 and H3K27ac, and repressive mark, H3K27me3. We investigated these histone marks in postmortem brains of controls and PD patients and observed that only H3K4me3 was significantly elevated at the SNCA promoter of the substantia nigra (SN) of PD patients both in punch biopsy as well as in NeuN positive neuronal nuclei samples. To understand the importance of H3K4me3 in regulation of α -synuclein, we developed CRISPR/dCas9-based locus-specific H3K4me3 demethylating system where the catalytic domain of JARID1A was recruited to the SNCA promoter. This CRISPR/dCas9 SunTag-JARID1A significantly reduced H3K4me3 at SNCA promoter and concomitantly decreased α -synuclein both in the neuronal cell line SH-SY5Y and idiopathic PD-iPSC derived dopaminergic neurons. In sum, this study indicates that α -synuclein expression in PD is controlled by SNCA's histone PTMs and modulation of the histone landscape of SNCA can reduce α -synuclein expression.

Induced pluripotent stem cells (iPSCs) as game‐changing tools in the treatment of neurodegenerative disease: Mirage or reality?

“…The use of PD‐patient‐derived iPSCs will help researchers to recognize the involved genes and mutations in the PD pathogenesis and subsequently identify the molecular mechanisms that participate in PD progression (Stoddard‐Bennett & Pera, 2020). In the last years, synuclein α (SNCA), β‐glucosidase (GBA), leucine‐rich repeat kinase 2 (LRPK2), parkin RBR E3 ubiquitin‐protein ligase (PARK2) and PTEN‐induced kinase 1 (PINK1) mutations have frequently been explored in genetic PD iPSCs (Guhathakurta et al, 2020; Kaavya et al, 2020; Kang, Tang, & Guo, 2016). Investigators try to clarify the pathological character of not only dopaminergic neurons but also other genetic PD iPSCs‐derived neuronal cells.…”

Caracterização epigenética nos núcleos respiratórios no modelo animal 6-OHDA da doença de Parkinson.

“…tanto em células de neuroblastoma SHSY5Y, bem como em neurônios dopaminérgicos de pacientes com DP. Estes resultados implicam na importância da H3K4me3 na regulação de alfa-sinucleína em DP(GUHATHAKURTA et al, 2020). De fato, alguns estudos mostraram que os níveis de H3K27me3 diminuíram na SN após a injeção…”

“…pacientes com DP(GUHATHAKURTA et al, 2020;PAVLOU;OUTEIRO, 2017) e que ao remover a metilação ocasionou uma queda significante nos níveis de alfa-sinucleína, baseado na técnica de CRISPR/dCas9 que efetivamente reduziu o enriquecimento de H3K4me3 do promotor do gene SNCA (alfa-sinucleína) e concomitantemente diminuiu os 29 níveis de proteína condensação da estrutura da cromatina que impede o acesso do fator de transcrição ao DNA, levando à repressão da transcrição (HARRISON; DEXTER, 2013a) (Fig.2B). Porém, há um equilíbrio rigidamente controlado entre os efeitos das HATs e HDACs, permitindo a (des) acetilação das histonas e o controle dinâmico da transcrição do gene (DIETZ; CASACCIA, 2010; SAHA;PAHAN, 2006).…”