HUWE1 regulates mitophagy to protect dopaminergic neurons from 6-OHDA- and MPP⁺-induced neurotoxicity
Chanhaeng Lee, Dong Yeol Kim, Sang-Min Kim, Inn-Oc Han
TL;DR
This study shows that HUWE1 helps protect brain cells from damage linked to Parkinson's disease by managing mitochondrial health.
Contribution
The study identifies HUWE1 as a novel regulator of mitophagy in dopaminergic neurons under neurotoxic stress.
Findings
HUWE1 depletion increases vulnerability of dopaminergic neurons to 6-OHDA and MPP⁺ toxicity.
Overexpression of HUWE1 preserves mitochondrial integrity and promotes mitophagy under stress.
BL-918 treatment activates HUWE1-mediated mitophagy and reduces neurotoxic effects.
Abstract
Parkinson’s disease (PD) is characterized by dopaminergic neuronal loss, often associated with mitochondrial dysfunction and impaired mitophagy. Here, we investigated the role of HUWE1, an E3 ubiquitin ligase, in regulating mitophagy and neuronal survival in a cellular PD model. HUWE1 promoted mitophagy, whereas its depletion sensitized SH-SY5Y cells to 6-hydroxydopamine (6-OHDA)- and 1-methyl-4-phenylpyridinium (MPP⁺)-induced cytotoxicity and mitochondrial dysfunction. Notably, both toxins downregulated HUWE1, suggesting that loss of HUWE1 contributes to dopaminergic vulnerability. Conversely, HUWE1 overexpression preserved mitochondrial integrity and enhanced mitophagy under neurotoxic stress. Importantly, BL-918, a ULK1 activator that promotes AMBRA1 recruitment, facilitated HUWE1-mediated mitophagy in SH-SY5Y cells. BL-918 treatment significantly attenuated 6-OHDA- and MPP⁺-induced…
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Taxonomy
TopicsAutophagy in Disease and Therapy · Parkinson's Disease Mechanisms and Treatments · Protein Degradation and Inhibitors