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

• Published in: Neuropharmacology 2021-08, Vol.194, p.108372-108372, Article 108372
• Main Authors: Srivastava, Anup K., Choudhury, Subhasree Roy, Karmakar, Surajit
• Format: Article
• Language: English
• Subjects: Alpha-synuclein; alpha-Synuclein - metabolism; Animals; BMI-1; Brain - metabolism; Cell Line, Tumor; Epigenetic polycomb repressor complex; Female; Humans; Melatonin - pharmacology; Mice; Mice, Inbred BALB C; Models, Animal; Neuroprotection; Parkinson Disease - metabolism; Parkinson's disease; Phosphorylation; Polycomb Repressive Complex 1 - metabolism; Polycomb-Group Proteins - metabolism; Proteasome Endopeptidase Complex - drug effects; Rats; Rotenone - pharmacology; Ubiquitin-dependent proteasome pathway; Ubiquitination - physiology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2020.108372

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 suppressing pα-SYN (S129) level turns ineffective upon depletion of neuronal BMI-1. However, it has been observed that our neuroprotectant exposure suppresses the cellular pα-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 pα-SYN (S129), respectively. Furthermore, our investigation reveals that accumulated pα-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 α-SYN and suspected to be a novel therapeutic target in PD. [Display omitted] •Neuronal BMI1 established as negative regulator of α-synuclein (α-SYN).•Melatonin exposure elicits both BMI1 expression and associated E3 ubiquitin (Ub) activity (H2AK119ub).•BMI1 expression required for Mel induced downregulation of pα-SYN (S129).•Regulatory BMI1- pα-SYN (S129) interaction promotes ubiquitin dependent proteasomal activation.