Saturated Proteostasis and Nuclear Injuries Defeat Homeostatic Potentials of α-Synuclein Filaments
Biogenesis of inclusion bodies (IBs) contributes to protein quality control (PQC). Perinuclear IBs like aggresomes/JUNQs serve as sites for ubiquitin-proteasome mediated protein degradation. The other canonical IB, IPOD, does not degrade but sequesters non-ubiquitinated terminally aggregated proteins to prevent their promiscuous interactions and interferences with other cellular functions. Here, we show that as a deviation from this convention, misfolding-prone α-Synuclein is simultaneously deposited into two distinct IBs - Syn-aggresomes and seeding based filamentous inclusions (Syn-filaments), both acting as sites for ubiquitin-proteasome mediated protein degradation. Syn-aggresomes buffer the spontaneous turnover of α-Synuclein. Syn-filaments serve the dual purpose of self-sequestration and opportunistic degradation. Counterintuitively, overgrowth of perinuclear Syn-filaments titrates out cellular PQC-pool and challenges the turnover and solubility of other misfolding-prone proteins. Moreover, large Syn-filaments associate with LaminB1, mount mechanical stress on nuclear envelope via dynein, disrupt nuclear integrity, and deregulate stress-triggered transcription of chaperones failing their homeostatic potential.