@article{a94813b69f7640408947bf9053a80c7a,
title = "NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility",
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.",
author = "Gleixner, {Amanda M.} and Verdone, {Brandie Morris} and Otte, {Charlton G.} and Anderson, {Eric N.} and Nandini Ramesh and Shapiro, {Olivia R.} and Gale, {Jenna R.} and Mauna, {Jocelyn C.} and Mann, {Jacob R.} and Copley, {Katie E.} and Daley, {Elizabeth L.} and Ortega, {Juan A.} and Cicardi, {Maria Elena} and Evangelos Kiskinis and Julia Kofler and Pandey, {Udai B.} and Davide Trotti and Donnelly, {Christopher J.}",
note = "Funding Information: We appreciated the generosity of Akiko Takedo for sharing the NUP62 plasmid utilized in this study. This work was supported by grants from the NIH (R01NS105756 to CJD and R21NS098379 to CJD and UB, R01NS104219 to EK), the LiveLikeLou Center for ALS Research at the University of Pittsburgh Brain Institute, a fellowship and grants from Target ALS Foundation and the Frick Foundation for ALS Research, the Genentech Charitable Foundation, and a generous gift from Barbara McCormick to CJD. AMG was supported by the Milton Safenowitz Postdoctoral Fellowship for ALS Research of the ALS Association and NIH T32 Postdoctoral Training Fellowship Recipient (NS086749). JRM was supported by a fellowship from the Center for Protein Conformational Diseases at the University of Pittsburgh. DT was supported by grants from MDA (#628389) and NIH R21-NS090912. DT, BMV, and MEC were also supported by the Farber Family Foundation and the Family Strong 4 ALS foundation. JAO is an AFM-Telethon Postdoctoral Research Fellow. EK is a Les Turner ALS Center Investigator and a New York Stem Cell Foundation-Robertson Investigator. JK and the brain bank at the University of Pittsburgh are supported by NIA P30 AG066468. Funding Information: We appreciated the generosity of Akiko Takedo for sharing the NUP62 plasmid utilized in this study. This work was supported by grants from the NIH (R01NS105756 to CJD and R21NS098379 to CJD and UB, R01NS104219 to EK), the LiveLikeLou Center for ALS Research at the University of Pittsburgh Brain Institute, a fellowship and grants from Target ALS Foundation and the Frick Foundation for ALS Research, the Genentech Charitable Foundation, and a generous gift from Barbara McCormick to CJD. AMG was supported by the Milton Safenowitz Postdoctoral Fellowship for ALS Research of the ALS Association and NIH T32 Postdoctoral Training Fellowship Recipient (NS086749). JRM was supported by a fellowship from the Center for Protein Conformational Diseases at the University of Pittsburgh. DT was supported by grants from MDA (#628389) and NIH R21-NS090912. DT, BMV, and MEC were also supported by the Farber Family Foundation and the Family Strong 4 ALS foundation. JAO is an AFM-Telethon Postdoctoral Research Fellow. EK is a Les Turner ALS Center Investigator and a New York Stem Cell Foundation-Robertson Investigator. JK and the brain bank at the University of Pittsburgh are supported by NIA P30 AG066468. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-31098-6",
language = "English (US)",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}