Widespread Nuclear Lamina injuries defeat proteostatic purposes of α-Synuclein amyloid Inclusions.

Biogenesis of inclusion bodies (IBs) facilitates protein quality control (PQC). Canonical aggresomes execute degradation of misfolded proteins while non-degradable amyloids quarantine into Insoluble Protein Deposits. Lewy Bodies (LBs) are filamentous amyloid inclusions of α-Synuclein but PQC-benefits and drawbacks associated with LB-like IBs remain underexplored. Here, we report that a crosstalk between filamentous LB-like IBs and aggresome-like IBs of α-Synuclein (Syn-aggresomes) buffer the load, aggregation state, and turnover of the amyloidogenic protein. Filamentous LB-like IBs possess unorthodox PQC-capacities of self-quarantining α-Synuclein amyloids and being degradable upon receding fresh amyloidogenesis. Syn-aggresomes equilibrate biogenesis of filamentous LB-like IBs by facilitating spontaneous degradation of α-Synuclein and conditional turnover of disintegrated α-Synuclein amyloids. Thus, both the inclusion bodies primarily contribute to PQC. Incidentally, the overgrown perinuclear LB-like IBs turn degenerative once these are misidentified by BICD2, a cargo-adapter for cytosolic motor-protein dynein. Microscopy indicates that microtubules surrounding the perinuclear filamentous inclusions are also distorted misbalancing the cytoskeleton-nucleoskeleton tension leading to widespread lamina injuries. Together, nucleocytoplasmic mixing, DNA-damage, and deregulated transcription of stress chaperones defeat the proteostatic purposes of the filamentous amyloids of α-Synuclein.