Neuronal Bmi-1 is critical for melatonin induced ubiquitination and proteasomal degradation of α-synuclein in experimental Parkinson's disease models.

Abstract 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 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 α-synuclein protein phosphorylated at serine 129 (pα-SYN (S129). In general, neuroprotectant suppress pα-SYN (S129) level turns ineffective upon depletion of neuronal BMI-1. Neuroprotectant exposure suppresses the cellular pα-SYN (S129) and maintains the BMI-1 level. The pharmacological inhibition and activation of proteasomal machinery promote the cellular accumulation and degradation of neuronal pα-SYN (S129), respectively. Mechanistically, accumulated pα-SYN (S129) priorly complexed with BMI-1 undergoes ubiquitin-dependent proteasomal degradation. These findings linked the unestablished non-canonical role of BMI-1 in the clearance of pathological α-SYN and suspected to be a novel therapeutic target in PD.