Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS.
Alyssa N CoyneVictoria BaskervilleBenjamin L ZaepfelDennis W DicksonFrank RigoC Frank BennettC Patrick LuskJeffrey D RothsteinPublished in: Science translational medicine (2021)
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.
Keyphrases
- amyotrophic lateral sclerosis
- endothelial cells
- high glucose
- quality control
- stem cells
- oxidative stress
- induced pluripotent stem cells
- diabetic rats
- spinal cord
- pluripotent stem cells
- early onset
- drug induced
- signaling pathway
- big data
- machine learning
- genome wide
- mesenchymal stem cells
- artificial intelligence
- dna methylation
- subarachnoid hemorrhage
- brain injury
- cerebral ischemia
- human health