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NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility
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NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility
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Journal Article
NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility
2022
Overview
A G4C2 hexanucleotide repeat expansion in the
C9orf72
gene is the most common genetic cause of ALS and FTLD (C9-ALS/FTLD) with cytoplasmic TDP-43 inclusions observed in regions of neurodegeneration. The accumulation of repetitive RNAs and dipeptide repeat protein (DPR) are two proposed mechanisms of toxicity in C9-ALS/FTLD and linked to impaired nucleocytoplasmic transport. Nucleocytoplasmic transport is regulated by the phenylalanine-glycine nucleoporins (FG nups) that comprise the nuclear pore complex (NPC) permeability barrier. However, the relationship between FG nups and TDP-43 pathology remains elusive. Our studies show that nuclear depletion and cytoplasmic mislocalization of one FG nup, NUP62, is linked to TDP-43 mislocalization in C9-ALS/FTLD iPSC neurons. Poly-glycine arginine (GR) DPR accumulation initiates the formation of cytoplasmic RNA granules that recruit NUP62 and TDP-43. Cytoplasmic NUP62 and TDP-43 interactions promotes their insolubility and NUP62:TDP-43 inclusions are frequently found in C9orf72 ALS/FTLD as well as sporadic ALS/FTLD postmortem CNS tissue. Our findings indicate NUP62 cytoplasmic mislocalization contributes to TDP-43 proteinopathy in ALS/FTLD.
ALS and FTLD are both characterized by insoluble cytoplasmic depositions of TDP43. Here the authors show that the nucleopore protein NUP62 is mislocalized in C9orf72 and sporadic ALS/FTLD and propose that it interacts with TDP-43 to promote its insolubility.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ Amyotrophic lateral sclerosis
/ Amyotrophic Lateral Sclerosis - metabolism
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Frontotemporal Lobar Degeneration - metabolism
/ Glycine
/ Humanities and Social Sciences
/ Humans
/ Insects
/ Medicine
/ Mutation
/ Proteins
/ Science
/ Toxicity
