Modeling UBQLN2-mediated neurodegenerative disease in mice: Shared and divergent properties of wild type and mutant UBQLN2 in phase separation, subcellular localization, altered proteostasis pathways, and selective cytotoxicity.

Modeling UBQLN2-mediated neurodegenerative disease in mice: Shared and divergent properties of wild type and mutant UBQLN2 in phase separation, subcellular localization, altered proteostasis pathways, and selective cytotoxicity.
Neurobiol Dis. 2020 Jul 09;:105016
Authors: Sharkey LM, Sandoval-Pistorius SS, Moore SJ, Gerson JE, Komlo R, Fischer S, Negron-Rios KY, Crowley EV, Padron F, Patel R, Murphy GG, Paulson HL
Abstract
The ubiquitin-binding proteasomal shuttle protein UBQLN2 is implicated in common neurodegenerative disorders due to its accumulation in disease-specific aggregates and, when mutated, directly causes familial frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). Like other proteins linked to FTD/ALS, UBQLN2 undergoes phase separation to form condensates. The relationship of UBQLN2 phase separation and accumulation to neurodegeneration, however, remains uncertain. Employing biochemical, neuropathological and behavioral assays, we studied the impact of overexpressing WT or mutant UBQLN2 in the CNS of transgenic mice. Expression of UBQLN2 harboring a pathogenic mutation (P506T) elicited profound and widespread intraneuronal inclusion formation and aggregation without prominent neurodegenerative or behavioral changes. Both WT and mutant UBQLN2 formed ubiquitin- and P62-positive inclusions in neurons, supporting the view that UBQLN2 is intrinsically prone to phase separate, with the size, shape and frequency o...

Source: Neurobiology of Disease - July 8, 2020 Category: Neurology Authors: Sharkey LM, Sandoval-Pistorius SS, Moore SJ, Gerson JE, Komlo R, Fischer S, Negron-Rios KY, Crowley EV, Padron F, Patel R, Murphy GG, Paulson HL Tags: Neurobiol Dis Source Type: research