Affiliation:
1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences Soochow University Suzhou China
2. Department of Physiology & Medical Physics and FUTURE‐NEURO Research Centre Royal College of Surgeons in Ireland Dublin Ireland
3. Faculty of Health Sciences University of Macau Macau China
4. Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine Jiangsu Institute of Nuclear Medicine Wuxi China
Abstract
AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two aging‐related neurodegenerative diseases that share common key features, including aggregation of pathogenic proteins, dysfunction of mitochondria, and impairment of autophagy. Mutations in ubiquilin 2 (UBQLN2), a shuttle protein in the ubiquitin‐proteasome system (UPS), can cause ALS/FTD, but the mechanism underlying UBQLN2‐mediated pathogenesis is still uncertain. Recent studies indicate that mitophagy, a selective form of autophagy which is crucial for mitochondrial quality control, is tightly associated with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and ALS. In this study, we show that after Parkin‐dependent ubiquitination of damaged mitochondria, UBQLN2 is recruited to poly‐ubiquitinated mitochondria through the UBA domain. UBQLN2 cooperates with the chaperone HSP70 to promote UPS‐driven degradation of outer mitochondrial membrane (OMM) proteins. The resulting rupture of the OMM triggers the autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. UBQLN2 is required for Parkin‐mediated mitophagy and neuronal survival upon mitochondrial damage, and the ALS/FTD pathogenic mutations in UBQLN2 impair mitophagy in primary cultured neurons. Taken together, our findings link dysfunctional mitophagy to UBQLN2‐mediated neurodegeneration.
Funder
Erasmus+
National Natural Science Foundation of China
Priority Academic Program Development of Jiangsu Higher Education Institutions
Publisher
Springer Science and Business Media LLC
Subject
Genetics,Molecular Biology,Biochemistry
Cited by
7 articles.
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