期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 13, 期 604, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abe1923
关键词
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资金
- NIH [P01NS099114, U54NS091046, R01NS094239, R01NS122236, K99NS123242]
- Department of Defense
- Robert Packard Center for ALS Research Answer ALS Program
- ALS Finding a Cure
- ALS Association
- Muscular Dystrophy Association
- Virginia Gentleman Foundation
- F Prime
- Chan Zuckerberg Initiative
- ALSA Milton Safenowitz Postdoctoral Fellowship
Alterations in the components and function of the nuclear pore complex have been implicated in the pathogenesis of genetic forms of neurodegeneration, and CHMP7 has been identified as a critical mediator of NPC quality control. Increasing evidence suggests that altered CHMP7-mediated Nup homeostasis may play a prominent role in the development of familial and sporadic ALS, highlighting CHMP7 as a potential therapeutic target.
Alterations in the components [nucleoporins (Nups)] and function of the nuclear pore complex (NPC) have been implicated as contributors to the pathogenesis of genetic forms of neurodegeneration including C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). We hypothesized that Nup alterations and the consequential loss of NPC function may lie upstream of TDP-43 dysfunction and mislocalization widely observed in ALS, FTD, and related neurodegenerative diseases. Here, we provide evidence that CHMP7, a critical mediator of NPC quality control, is increased in nuclei of C9orf72 and sporadic ALS induced pluripotent stem cell (iPSC)-derived spinal neurons (iPSNs) and postmortem human motor cortex before the emergence of Nup alterations. Inhibiting the nuclear export of CHMP7 triggered Nup reduction and TDP-43 dysfunction and pathology in human neurons. Knockdown of CHMP7 alleviated disease-associated Nup alterations, deficits in Ran GTPase localization, defects in TDP-43-associated mRNA expression, and downstream glutamate-induced neuronal death. Thus, our data support a role for altered CHMP7-mediated Nup homeostasis as a prominent initiating pathological mechanism for familial and sporadic ALS and highlight the potential for CHMP7 as therapeutic target.
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