Human Ubiquilin 2 and TDP-43 copathology drives neurodegeneration in transgenic Caenorhabditis elegans
Open Access
- 8 May 2021
- journal article
- research article
- Published by Oxford University Press (OUP) in G3 Genes|Genomes|Genetics
- Vol. 11 (8)
- https://doi.org/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 an 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.Keywords
Funding Information
- Department of Veterans Affairs (I01BX003755)
- National Institutes of Health (R01NS064131)
- University of Nebraska Kearney Biology Department
- Graduate Student Research Grant
This publication has 38 references indexed in Scilit:
- Ubiquilin 2mutations in Italian patients with amyotrophic lateral sclerosis and frontotemporal dementiaJournal of Neurology, Neurosurgery & Psychiatry, 2012
- UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosisNeurobiology of Aging, 2012
- Does a loss of TDP-43 function cause neurodegeneration?Molecular Neurodegeneration, 2012
- Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementiaNature, 2011
- Phosphorylation Promotes Neurotoxicity in aCaenorhabditis elegansModel of TDP-43 ProteinopathyJournal of Neuroscience, 2010
- The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS)Human Molecular Genetics, 2010
- Ubiquilin Modifies TDP-43 Toxicity in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS)*Online Journal of Public Health Informatics, 2010
- Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathiesActa Neuropathologica, 2009
- The Ubiquitin-associated Domain of hPLIC-2 Interacts with the ProteasomeMolecular Biology of the Cell, 2003
- Assignment1 of Ubiquilin2 (UBQLN2) to human chromosome Xp11.23→p11.1 by GeneBridge radiation hybridsCytogenetic and Genome Research, 2000