Nuclear-injuries by aberrant dynein-forces defeat proteostatic purposes of Lewy Body-like InclusionsNuclear-injuries by aberrant dynein-forces defeat proteostatic purposes of Lewy Body-like 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 well-known neurodegenerative IBs of α-Synuclein but PQC-benefits and drawbacks associated with LBs remain underexplored. Here, we report that a crosstalk between LBs and aggresome-like IBs of α-Synuclein (Syn-aggresomes) buffer amyloidogenic α-Synuclein load. LBs possess unorthodox PQC-capacities of self-quarantining Syn-amyloids and being degradable upon receding fresh amyloidogenesis. Syn-aggresomes equilibrate biogenesis of LBs by facilitating spontaneous degradation of soluble α-Synuclein and opportunistic turnover of Syn-amyloids. LBs overgrow at the perinucleus once amyloidogenesis sets in and are misidentified by cytosolic BICD2 as cargos for motor-protein dynein. Simultaneously, microtubules surrounding the perinuclear LBs are distorted misbalancing the dynein motor-force on nucleoskeleton leading to widespread lamina injuries. Like typical Laminopathies, nucleocytoplasmic mixing, DNA-damage, and deregulated transcription of stress chaperones defeat the proteostatic purposes of LBs.