Neuronal Expression of UBQLN2 Exacerbates TDP-43 Pathology in TDP-43 Mice through Interaction with Ubiquitin.

TitleNeuronal Expression of UBQLN2 Exacerbates TDP-43 Pathology in TDP-43 Mice through Interaction with Ubiquitin.
Publication TypeJournal Article
Year of Publication2018
AuteursPicher-Martel, V, Renaud, L, Bareil, C, Julien, J-P
JournalMol Neurobiol
Date Published2018 Oct 30
ISSN1559-1182
Abstract

Mutations in the gene encoding ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 up-regulation exacerbates TDP-43 cytoplasmic aggregates. To analyze interaction between UBQLN2 and TDP-43 and to produce a relevant ALS animal model, we have generated a new transgenic mouse expressing UBQLN2 under the neurofilament heavy (NFH) gene promoter. The UBQLN2 mice were then bred with our previously described TDP-43 mice to generate double-transgenic UBQLN2; TDP-43 mice. With low-expression levels of UBQLN2, the double-transgenic mice developed TDP-43 cytosolic accumulations in motor neurons starting at 5 months of age. These double-transgenic mice exhibited motor neuron loss, muscle atrophy, as well as motor and cognitive deficits during aging. The microglia from double-transgenic mice were hyperresponsive to intraperitoneal injection of lipopolysaccharide (LPS). In vivo and in vitro analyses suggested that extra UBQLN2 proteins can exacerbate cytoplasmic TDP-43 accumulations by competing with the UPS for binding to ubiquitin. Thus, increasing the pool of ubiquitin promoted the UPS function with ensuing reduction of TDP-43 cytosolic accumulations. In conclusion, the double-transgenic UBQLN2; TDP-43 mice provides a unique mouse model of ALS/FTD with enhanced TDP-43 pathology that can be exploited for drug testing.

DOI10.1007/s12035-018-1411-3
Alternate JournalMol. Neurobiol.
PubMed ID30377984
Grant List143275 / / Canadian Insitutes of health research /