RRC ID 71759
Author Gleixner AM, Verdone BM, Otte CG, Anderson EN, Ramesh N, Shapiro OR, Gale JR, Mauna JC, Mann JR, Copley KE, Daley EL, Ortega JA, Cicardi ME, Kiskinis E, Kofler J, Pandey UB, Trotti D, Donnelly CJ.
Title NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility.
Journal Nat Commun
Abstract 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.
Volume 13(1)
Pages 3380
Published 2022-6-13
DOI 10.1038/s41467-022-31098-6
PII 10.1038/s41467-022-31098-6
PMID 35697676
PMC PMC9192689
MeSH Amyotrophic Lateral Sclerosis* / metabolism C9orf72 Protein / genetics DNA Repeat Expansion DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Dipeptides / metabolism Frontotemporal Lobar Degeneration* / metabolism Glycine / genetics Humans
IF 12.121
Mice RBRC01828