TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
Abstract Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which impaired NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified Ref(2)p/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy of Drosophila tissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72-HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.
Cunningham Kathleen M.、Lloyd Thomas E.、Zhang Ke、Senturk Mumine、Sung Hyun、Rothstein Jeffrey D.、Zuo Zhongyuan、Bellen Hugo J.、Maulding Kirstin、Grima Jonathan、Ruan Kai、Song Helen
Cellular and Molecular Medicine Program, School of Medicine, Johns Hopkins UniversityCellular and Molecular Medicine Program, School of Medicine, Johns Hopkins University||Department of Neurology, School of Medicine, Johns Hopkins University||Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins UniversityDepartment of Neurology, School of Medicine, Johns Hopkins UniversityProgram in Developmental Biology, Baylor College of Medicine (BCM)Department of Neurology, School of Medicine, Johns Hopkins UniversityCellular and Molecular Medicine Program, School of Medicine, Johns Hopkins University||Department of Neurology, School of Medicine, Johns Hopkins University||Brain Science Institute, School of Medicine, Johns Hopkins University||Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins UniversityDepartment of Molecular and Human GeneticsProgram in Developmental Biology, Baylor College of Medicine (BCM)||Department of Molecular and Human Genetics||Department of Neuroscience||Jan and Dan Duncan Neurological Research Institute, Texas Children?ˉs Hospital||Howard Hughes Medical InstituteCellular and Molecular Medicine Program, School of Medicine, Johns Hopkins UniversityBrain Science Institute, School of Medicine, Johns Hopkins University||Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins UniversityDepartment of Neurology, School of Medicine, Johns Hopkins UniversityDepartment of Neurology, School of Medicine, Johns Hopkins University
神经病学、精神病学基础医学分子生物学
Cunningham Kathleen M.,Lloyd Thomas E.,Zhang Ke,Senturk Mumine,Sung Hyun,Rothstein Jeffrey D.,Zuo Zhongyuan,Bellen Hugo J.,Maulding Kirstin,Grima Jonathan,Ruan Kai,Song Helen.TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/2020.06.26.173021.点此复制
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