Saturated Proteostasis and Nuclear Injuries Defeat Homeostatic Potentials of α-Synuclein Filaments

Abstract

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 -Synuclein associated diseases like Dementia with Lewy bodies (DLB) and Parkinsons disease. Intriguingly, the PQC benefits and drawbacks associated with LBs remain underexplored. Here, we report that the crosstalk between LBs and aggresome-like IBs of -Synuclein (Syn-aggresomes) buffers amyloidogenic -Synuclein load in primary neurons and mitotic cell models. Using cellular biochemistry, genetic knockdown, and microscopy tools we find that LBs possess unorthodox PQC-capacities of self-quarantining the Syn-amyloids, and being degradable upon receding fresh amyloidogenesis. Syn-aggresomes equilibrate biogenesis of LBs by facilitating spontaneous and opportunistic turnover of soluble -Synuclein and Syn-amyloids, respectively. However, 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 lamina injuries. Like typical Laminopathies, nucleocytoplasmic mixing, DNA-damage, and deregulated transcription of stress chaperones defeat the proteostatic purposes of LBs. We confirmed the lamina disintegrities in brain sections of Parkinsons disease patients. Together, our study provides insights into the intricate complexities of proteostatic possibilities associated with -Synuclein inclusions and offers understanding on the proteostasis-sensitivity of LB-containing aging neurons via lamina-injuries. Significance statementAmyloid inclusions of -Synuclein called Lewy Bodies (LBs) are hallmark of multiple neurodegenerative diseases like Dementia with Lewy Bodies and Parkinsons disease. A significant reason for the degeneration of LB-containing aging neurons in these diseases is their sensitivity to proteostasis stresses. We find two distinct inclusions of -Synuclein in the same neurons/cells. First, the Syn-aggresomes titrate the biogenesis of the other i.e., the LBs, by facilitating degradation of soluble -Synuclein. Syn-amyloids deposited in LBs remain degradable but LBs overgrow at the perinucleus once the kinetics of amyloid-biogenesis exceeds aggresome-assisted degradation of -Synuclein. Perinuclear LBs destabilize local tubulin-meshwork and are misidentified as cargo for cytosolic motor dynein. Aberrant cytoskeleton-nucleoskeleton tension disintegrates lamina, deregulates stress-responsive transcription, and triggers proteostasis-sensitivity in LB-containing neurons.