?-Synuclein A53T Binds to Transcriptional Adapter 2-Alpha and Blocks Histone H3 Acetylation.

?-Synuclein (?-syn) is a hallmark amyloidogenic protein component of Lewy bodies in dopaminergic neurons affected by Parkinson's disease (PD). Despite the multi-faceted gene regulation of ?-syn in the nucleus, the mechanism underlying ?-syn crosstalk in chromatin remodeling in PD pathogenesis remains elusive. Here, we identified transcriptional adapter 2-alpha (TADA2a) as ...
a novel binding partner of ?-syn using the BioID system. TADA2a is a component of the p300/CBP-associated factor and is related to histone H3/H4 acetylation. We found that ?-syn A53T was more preferentially localized in the nucleus than the ?-syn wild-type (WT), leading to a stronger disturbance of TADA2a. Indeed, ?-syn A53T significantly reduced the level of histone H3 acetylation in SH-SY5Y cells; its reduction was also evident in the striatum (STR) and substantia nigra (SN) of mice that were stereotaxically injected with ?-syn preformed fibrils (PFFs). Interestingly, ?-syn PFF injection resulted in a decrease in TADA2a in the STR and SN of ?-syn PFF-injected mice. Furthermore, the levels of TADA2a and acetylated histone H3 were significantly decreased in the SN of patients with PD. Therefore, histone modification through ?-syn A53T-TADA2a interaction may be associated with ?-syn-mediated neurotoxicity in PD pathology.
Mesh Terms:
Acetylation, Animals, Cell Line, Tumor, Corpus Striatum, DNA-Binding Proteins, Disease Models, Animal, Dopaminergic Neurons, Histones, Humans, Lewy Bodies, Male, Mice, Mice, Inbred C57BL, Nerve Degeneration, Parkinson Disease, Substantia Nigra, Transcription Factors, alpha-Synuclein
Int J Mol Sci
Date: May. 20, 2021
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