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

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          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.

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          Author and article information

          Journal
          G3 (Bethesda)
          G3 (Bethesda, Md.)
          Oxford University Press (OUP)
          2160-1836
          2160-1836
          Aug 07 2021
          : 11
          : 8
          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.
          Article
          6272515
          10.1093/g3journal/jkab158
          8496285
          33963840
          4b36d3ef-d782-4f36-a89e-62e64a819363
          History

          transgenic,neurodegeneration,amyotrophic lateral sclerosis,UBQLN2,TDP-43, C. elegans

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