CYCLINS, HSPs AND E3 LIGASE ACTIVITY IN CELL CYCLE DEREGULATION IN NEURO-MUSCULAR DEGENERATION

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative disorder after Alzheimer’s disease with approximately 7 million patients worldwide which are predicted to get doubled by 2030. The most common form of PD is the sporadic form with no known cause. Amongst many factors responsible for the pathogenesis of sporadic PD, Cell cycle reentry (CCE) with subsequent DNA synthesis in at-risk dopaminergic neurons has been recently identified as the cause of neuronal cell death. Neurons are post-mitotic cells which never divide, but in lieu of their physiological demands certain cell cycle proteins are utilized. However, under the influence of various stressors cell cycle is re-activated in a full blown manner and owing to mitotic incompetence of neurons, drive them to death. Mounting evidence has outlined the causal role of CCE in the pathogenesis of PD and other neurodegenerative disorders. Moreover, certain protective proteins such as ubiquitin E3 ligases and heat shock proteins play crucial role in maintaining protein homeostasis and in alleviating toxic protein burden in various neurodegenerative disorders thereby, promoting neuronal cell survival. The present work aims to study the involvement of cell cycle proteins in neuronal apoptosis and to underline the role of protective proteins especially HSP70 in neuronal cell viability. The study uses widely known toxin rotenone to mimic PD in SH-SY5Y neuroblastoma cell lines. The results show upregulation of cyclin E with subsequent attenuation of ubiquitin E3 ligase parkin and HSP70 in response to rotenone administration. Further, screening of HSP70 inducing biomolecules have clearly outlined their neuroprotective potential in attenuating CCE led neuronal death and in modifying and reversing rotenone induced toxicity. Thus, the present work opens up a new avenue of using HSP70 inducing compounds to target CCE mediated neuronal death in PD which can be extended to other neurodegenerative disorders