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

Sci Transl Med. 2021 Jul 28;13(604):eabe1923. 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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • C9orf72 Protein / genetics
  • DNA-Binding Proteins / genetics
  • Endosomal Sorting Complexes Required for Transport
  • Frontotemporal Dementia* / genetics
  • Humans
  • Nuclear Pore


  • C9orf72 Protein
  • CHMP7 protein, human
  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • TARDBP protein, human

Supplementary concepts

  • Amyotrophic Lateral Sclerosis 2, Juvenile