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

• Published in: Science translational medicine 2021-07, Vol.13 (604)
• Main Authors: Coyne, Alyssa N, Baskerville, Victoria, Zaepfel, Benjamin L, Dickson, Dennis W, Rigo, Frank, Bennett, Frank, Lusk, C Patrick, Rothstein, Jeffrey D
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Autopsy; C9orf72 Protein - genetics; Cortex (motor); Dementia disorders; DNA-Binding Proteins - genetics; Endosomal Sorting Complexes Required for Transport; Frontotemporal dementia; Frontotemporal Dementia - genetics; Gene expression; Homeostasis; Humans; Localization; Neurodegeneration; Neurodegenerative diseases; Nuclear Pore; Nuclear transport; Nucleoporins; Pluripotency; Quality control; Stem cells; Therapeutic targets
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.abe1923

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 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 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.