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Nat Commun ; 13(1): 3380, 2022 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-35697676

RESUMEN

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.


Asunto(s)
Esclerosis Amiotrófica Lateral , Degeneración Lobar Frontotemporal , Esclerosis Amiotrófica Lateral/metabolismo , Proteína C9orf72/genética , Expansión de las Repeticiones de ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Dipéptidos/metabolismo , Degeneración Lobar Frontotemporal/metabolismo , Glicina/genética , Humanos
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