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

Author

Listed:
  • Amanda M. Gleixner

    (University of Pittsburgh School of Medicine
    University of Pittsburgh Brain Institute)

  • Brandie Morris Verdone

    (Thomas Jefferson University)

  • Charlton G. Otte

    (University of Pittsburgh School of Medicine
    University of Pittsburgh Brain Institute
    University of Pittsburgh School of Medicine)

  • Eric N. Anderson

    (University of Pittsburgh Medical Center)

  • Nandini Ramesh

    (University of Pittsburgh Medical Center
    University of Pittsburgh Graduate School of Public Health)

  • Olivia R. Shapiro

    (University of Pittsburgh School of Medicine
    University of Pittsburgh Brain Institute)

  • Jenna R. Gale

    (University of Pittsburgh School of Medicine
    University of Pittsburgh Brain Institute)

  • Jocelyn C. Mauna

    (University of Pittsburgh School of Medicine
    University of Pittsburgh Brain Institute)

  • Jacob R. Mann

    (University of Pittsburgh School of Medicine
    University of Pittsburgh Brain Institute
    University of Pittsburgh)

  • Katie E. Copley

    (University of Pittsburgh School of Medicine
    University of Pittsburgh Brain Institute)

  • 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
    Northwestern University Feinberg School of Medicine)

  • Julia Kofler

    (University of Pittsburgh Brain Institute
    University of Pittsburgh)

  • Udai B. Pandey

    (University of Pittsburgh Brain Institute
    University of Pittsburgh Graduate School of Public Health
    University of Pittsburgh)

  • Davide Trotti

    (Thomas Jefferson University)

  • Christopher J. Donnelly

    (University of Pittsburgh School of Medicine
    University of Pittsburgh Brain Institute
    University of Pittsburgh)

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.

Suggested Citation

  • 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 , 2022. "NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31098-6
    DOI: 10.1038/s41467-022-31098-6
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    1. Hongyi Wu & Loo Chien Wang & Belle M. Sow & Damien Leow & Jin Zhu & Kathryn M. Gallo & Kathleen Wilsbach & Roshni Gupta & Lyle W. Ostrow & Crystal J. J. Yeo & Radoslaw M. Sobota & Rong Li, 2024. "TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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