202301Yabuki

研究発表を行った学会；第45回日本分子生物学会年会
2022年11月30日〜12月2日　（幕張メッセ）
タイトル； RNA グアニン四重鎖による α-シヌクレイン相転移促進メカニズム.
発表者；矢吹　悌氏
（熊本大学　発生医学研究所　ゲノム神経学分野）
要旨；
The mechanism underling dysfunction of cellular proteostasis on α-synuclein (α-Syn) leading to pathogenesis of a sporadic synucleinopathy remains unclear. We have reported that the binding of an RNA secondary structure G-quadruplex (G4RNA) to a prion-like protein FMRpolyG causes its liquid-to-solid phase transition, leading to neurodegeneration in a hereditary neurodegenerative disease (Sci Adv. 2021). Here, we introduce the possibility that G4RNA is a key pathogen on the phase transition of α-Syn. Purified α-Syn protein preferentially bound to guanine-rich RNA sequences by RNA Bind-N-Seq using a pool of random RNA oligonucleotides in vitro. We confirmed that purified α-Syn protein binds to G4 structure formed RNA specifically, but not other structures in EMSA. In addition, purified α-Syn protein underwent liquid-liquid phase separation, and the addition of G4RNA promoted the liquid-solid phase transition under molecular crowding. In mouse primary neurons, G4RNA assembly was immediately observed under cellular stress conditions, thereafter co-aggregation of α-Syn with G4RNA was occurred. Artificial assembly of G4RNA using an optogenetic approach initiated α-Syn aggregation, thereby elicits neuronal dysfunction in mouse primary neurons. These results suggest that G4RNA assembly evoked by various cellular stress triggers to develop aggregation of α-Syn, which may be a cellular mechanism underlying onset of a sporadic synucleinopathy. We now analyze relationship between G4RNA and α-Syn aggregation in vivo.