Abstract
α-Synuclein (α-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 α-syn in the nucleus, the mechanism underlying α-syn crosstalk in chromatin remodeling in PD pathogenesis remains elusive. Here, we identified transcriptional adapter 2-alpha (TADA2a) as a novel binding partner of α-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 α-syn A53T was more preferentially localized in the nucleus than the α-syn wild-type (WT), leading to a stronger disturbance of TADA2a. Indeed, α-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 α-syn preformed fibrils (PFFs). Interestingly, α-syn PFF injection resulted in a decrease in TADA2a in the STR and SN of α-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 α-syn A53T-TADA2a interaction may be associated with α-syn-mediated neurotoxicity in PD pathology.
Highlights
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder, characterized phenotypically by motor abnormalities such as bradykinesia, rigidity, tremor, and neuropsychiatric disturbances resulting from selective dopaminergic neuronal death in the substantia nigra (SN) [1]. the majority of PD cases are sporadic or have no known causes, there are several autosomal dominant or recessive familial PD cases linked to genetic factors [2]
The accumulation of α-syn along the endoplasmic reticulum (ER) membrane triggers ER stress by interfering with intracellular trafficking and vesicle transport [2]. α-Syn accumulation at synaptic sites is considered the main cause of neuronal death in PD [5] and its mitochondrial localization in human dopaminergic neurons increases the production of reactive oxygen species (ROS) [6]
The results showed that transcriptional adapter 2-alpha (TADA2a) was predominantly localized in the nucleus, and a stronger signal of α-syn A53T compared with α-syn WT overlapped with TADA2a in the nucleus
Summary
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder, characterized phenotypically by motor abnormalities such as bradykinesia, rigidity, tremor, and neuropsychiatric disturbances resulting from selective dopaminergic neuronal death in the substantia nigra (SN) [1]. The formation of nuclear α-syn inclusions was identified in patients with multiple system atrophy, a well-known sporadic synucleinopathy [10,11]. We identified a novel interactome of α-syn wild-type (WT) and A53T, to help to expand our knowledge on the role of nuclear α-syn in neurotoxicity. We identified transcriptional adapter 2-alpha (TADA2a) as a novel binding partner of α-syn and found that α-syn A53T strongly blocked TADA2a activity, leading to reduced histone H3 acetylation. These results were confirmed using a mouse model of PD and in patients with PD
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