Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS.

Autor:	Coyne AN; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. jrothstein@jhmi.edu acoyne3@jhmi.edu.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Baskerville V; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Zaepfel BL; Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Dickson DW; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Rigo F; Ionis Pharmaceuticals, Carlsbad, CA 92010, USA., Bennett F; Ionis Pharmaceuticals, Carlsbad, CA 92010, USA., Lusk CP; Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA., Rothstein JD; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. jrothstein@jhmi.edu acoyne3@jhmi.edu.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2021 Jul 28; Vol. 13 (604).
DOI:	10.1126/scitranslmed.abe1923
Abstrakt:	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. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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