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Saxton AD, Kraemer BC. Human Ubiquilin 2 and TDP-43 copathology drives neurodegeneration in transgenic Caenorhabditis elegans. G3 (Bethesda). 2021;11(8)doi: 10.1093/g3journal/jkab158.
Saxton, A. D., & Kraemer, B. C. (2021). Human Ubiquilin 2 and TDP-43 copathology drives neurodegeneration in transgenic Caenorhabditis elegans. G3 (Bethesda, Md.), 11(8), . https://doi.org/10.1093/g3journal/jkab158
Saxton, Aleen D, and Kraemer, Brian C. "Human Ubiquilin 2 and TDP-43 copathology drives neurodegeneration in transgenic Caenorhabditis elegans." G3 (Bethesda, Md.) vol. 11,8 (2021). doi: https://doi.org/10.1093/g3journal/jkab158
Saxton AD, Kraemer BC. Human Ubiquilin 2 and TDP-43 copathology drives neurodegeneration in transgenic Caenorhabditis elegans. G3 (Bethesda). 2021 Aug 07;11(8). doi: 10.1093/g3journal/jkab158. PMID: 33963840; PMCID: PMC8496285.
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G3 (Bethesda). 2021 Aug 07;11(8). doi: 10.1093/g3journal/jkab158.

Human Ubiquilin 2 and TDP-43 copathology drives neurodegeneration in transgenic Caenorhabditis elegans.

G3 (Bethesda, Md.)

Aleen D Saxton, Brian C Kraemer

Affiliations

  1. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
  2. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA.
  3. Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
  4. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA.

PMID: 33963840 PMCID: PMC8496285 DOI: 10.1093/g3journal/jkab158

Abstract

Amyotrophic lateral sclerosis (ALS) is a debilitating, fatal neurodegenerative disease that causes rapid muscle wasting. It shares a spectrum of symptoms and pathology with frontotemporal lobar degeneration (FTLD). These diseases are caused by aberrant activity of a set of proteins including TDP-43 and UBIQUILIN-2 (UBQLN2). UBQLN2 encodes a ubiquitin-like adaptor protein involved in the ubiquitin-proteasome protein degradation pathway. Mutations in the PXX domain of UBQLN2 cause familial ALS. UBQLN2 aggregates in skein-like inclusions with other ALS and FTLD associated proteins including TDP-43 and ubiquitin. To facilitate further investigation of UBQLN2-mediated mechanisms of neurodegeneration, we made Caenorhabditis elegans transgenic lines pan-neuronally expressing human UBQLN2 cDNAs carrying either the wild-type UBQLN2 sequence or UBQLN2 with ALS causing mutations. Transgenic animals exhibit motor dysfunction accompanied by neurodegeneration of GABAergic motor neurons. At low levels of UBQLN2 expression, wild-type UBQLN2 causes significant motor impairment and neurodegeneration that is exacerbated by ALS associated mutations in UBQLN2. At higher levels of UBQLN2 expression, both wild-type and ALS mutated versions of UBQLN2 cause severe impairment. Molecular genetic investigation revealed that UBQLN2 dependent locomotor defects do not require the involvement of the endogenous homolog of TDP-43 in C. elegans (tdp-1). However, co-expression of wild-type human TDP-43 exacerbates UBQLN2 deficits. This model of UBQLN2-mediated neurodegeneration may be useful for further mechanistic investigation into the molecular cascades driving neurodegeneration in ALS and ALS-FTLD.

Published by Oxford University Press on behalf of Genetics Society of America 2021.

Keywords: C. elegans ; TDP-43; UBQLN2; amyotrophic lateral sclerosis; neurodegeneration; transgenic

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