NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility

Amanda M. Gleixner, Brandie Morris Verdone, Charlton G. Otte, Eric N. Anderson, Nandini Ramesh, Olivia R. Shapiro, Jenna R. Gale, Jocelyn C. Mauna, Jacob R. Mann, Katie E. Copley, Elizabeth L. Daley, Juan A. Ortega, Maria Elena Cicardi, Evangelos Kiskinis, Julia Kofler, Udai B. Pandey, Davide Trotti and Christopher J. Donnelly ()
Additional contact information
Amanda M. Gleixner: University of Pittsburgh School of Medicine
Brandie Morris Verdone: Thomas Jefferson University
Charlton G. Otte: University of Pittsburgh School of Medicine
Eric N. Anderson: University of Pittsburgh Medical Center
Nandini Ramesh: University of Pittsburgh Medical Center
Olivia R. Shapiro: University of Pittsburgh School of Medicine
Jenna R. Gale: University of Pittsburgh School of Medicine
Jocelyn C. Mauna: University of Pittsburgh School of Medicine
Jacob R. Mann: University of Pittsburgh School of Medicine
Katie E. Copley: University of Pittsburgh School of Medicine
Elizabeth L. Daley: Northwestern University of Feinberg School of Medicine
Juan A. Ortega: Northwestern University of Feinberg School of Medicine
Maria Elena Cicardi: Thomas Jefferson University
Evangelos Kiskinis: Northwestern University of Feinberg School of Medicine
Julia Kofler: University of Pittsburgh Brain Institute
Udai B. Pandey: University of Pittsburgh Brain Institute
Davide Trotti: Thomas Jefferson University
Christopher J. Donnelly: University of Pittsburgh School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31098-6

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