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

alpha-Synuclein (alpha-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 alpha-syn in the nucleus, the mechanism underlying alpha-syn crosstalk in chromatin remodeling in PD pathogenesis remains elusive. Here, we identified transcriptional adapter 2-alpha (TADA2a) as a novel binding partner of alpha-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 alpha-syn A53T was more preferentially localized in the nucleus than the alpha-syn wild-type (WT), leading to a stronger disturbance of TADA2a. Indeed, alpha-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 alpha-syn preformed fibrils (PFFs). Interestingly, alpha-syn PFF injection resulted in a decrease in TADA2a in the STR and SN of alpha-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 alpha-syn A53T-TADA2a interaction may be associated with alpha-syn-mediated neurotoxicity in PD pathology.

Automated summary

The interaction between alpha-syn A53T and TADA2a may lead to changes in histone modification, which are associated with neurotoxicity in the pathology of PD.