Srivastava AK, Choudhury SR, Karmakar S

Epigenetic polycomb repressor complex-1 subunit BMI-1 plays a pivotal role in the process of gene repression to maintain the self-renewal and differentiation state of neurogenic tissues. Accumulating reports links lower expression of BMI-1 fails to regulate the repression of anti-oxidant response genes disrupt mitochondrial homeostasis underlying neurodegeneration. Interestingly, this negative ...

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relation between BMI-1 function and neurodegeneration is distinct but has not been generalized as a potential biomarker particularly in Parkinson's disease (PD). Hyperphosphorylated BMI-1 undergoes canonical polycomb E3 ligase function loss, thereby leads to reduce monoubiquitylation of histone 2A at lysine 119 (H2AK119ub) corroborates cellular accumulation of ?-synuclein protein phosphorylated at serine 129 (p?-SYN (S129). In general, neuroprotectant suppressing p?-SYN (S129) level turns ineffective upon depletion of neuronal BMI-1. However, it has been observed that our neuroprotectant exposure suppresses the cellular p?-SYN (S129) and restore the the BMI-1 expression level in neuronal tissues. The pharmacological inhibition and activation of proteasomal machinery promote the cellular accumulation and degradation of neuronal p?-SYN (S129), respectively. Furthermore, our investigation reveals that accumulated p?-SYN (S129) are priorly complexed with BMI-1 undergoes ubiquitin-dependent proteasomal degradation and established as key pathway for therpeutic effect in PD. These findings linked the unestablished non-canonical role of BMI-1 in the clearance of pathological ?-SYN and suspected to be a novel therapeutic target in PD.

Date: Dec. 15, 2020

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