Sasazawa, Y. | Search bioRxiv

bioRxiv2025

Ubiquilin-2 liquid droplets catalyze α-synuclein fibril formation

Liquid-liquid phase separation (LLPS) and subsequent liquid-gel/solid transition are considered common aggregation mechanisms of proteins linked to neurodegenerative diseases. -synuclein (-syn), the main component of Parkinsons disease pathology, has been reported to undergo LLPS, thereby accelerating aggregate formation. However, the precise molecular events involved in the early stages of -syn aggregation remain controversial. In this study, we show that -syn aggregation is promoted by droplets formed by ubiquilin-2 (UBQLN2), rather than by -syn LLPS itself. During the liquid-gel/solid transition of UBQLN2 droplets, -syn within the droplets transformed into pathogenic fibrils both in vitro and in cells. Immunohistochemistry of brain sections from sporadic Parkinsons disease patients revealed UBQLN2 in substantia nigra Lewy bodies, implicating UBQLN2 in -syn aggregation in vivo. Furthermore, the small compound SO286 inhibited both UBQLN2 self-association and its interaction with -syn by binding to the STI1 domain, thereby suppressing -syn aggregation. These findings demonstrate that UBQLN2 droplets catalyze -syn fibrillization and suggest that small molecules targeting fibril-catalyzing proteins such as UBQLN2 may represent a novel therapeutic approach for neurodegenerative diseases.

biochemistry↗

bioRxiv2023

Identification of novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease

Autophagy-lysosome pathway plays an indispensable role in the intracellular protein quality control system, degrading abnormal organelles and proteins. Among these proteins is -Synuclein (Syn), which is associated with the pathogenesis of Parkinsons disease (PD). However, the activation of this lysosome-dependent degradation strategy is restricted by enzyme complementation. In this study, we focused on the phase of autophagosome-lysosome fusion around the microtubule organizing center (MTOC) that leads to Syn degradation. Through high-throughput chemical screening, we identified six clinically available drugs that enhance autophagy and can accumulate lysosomes around the MTOC from approximately 1,200 drugs screened. We further demonstrated that these compounds induce lysosomal clustering through a JIP4-TRPML1-dependent mechanism, which is associated with autophagy induction. Among these, the lysosomal clustering compound albendazole was observed to promote the autophagy-dependent degradation of Triton-X-insoluble proteasome inhibitor-induced aggregates (p62). In a cellular PD model, albendazole boosted the degradation of insoluble Syn, an effect that was reversed upon the addition of bafilomycin A1. Our results suggest that lysosomal clustering can facilitate the breakdown of protein aggregates. Therefore, compounds that promote lysosomal clustering may offer a promising therapeutic strategy against neurodegenerative diseases characterized by the presence of aggregate-prone proteins.

cell biology↗