1. Impaired 26S Proteasome Assembly Precedes Neuronal Loss in Mutant UBQLN2 Rats
- Author
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Wenjuan Zhang, Cao Huang, Limo Gao, and Bo Huang
- Subjects
0301 basic medicine ,Mutant ,medicine.disease_cause ,UBQLN2 ,0302 clinical medicine ,rat ,Biology (General) ,Amyotrophic lateral sclerosis ,Spectroscopy ,Neurons ,Mutation ,biology ,Chemistry ,Neurodegeneration ,FTD ,General Medicine ,Computer Science Applications ,Cell biology ,Cysteine Endopeptidases ,Frontotemporal Dementia ,Rats, Transgenic ,Proteasome Endopeptidase Complex ,QH301-705.5 ,Protein subunit ,Protein Aggregation, Pathological ,Catalysis ,Article ,protein aggregation ,Inorganic Chemistry ,03 medical and health sciences ,medicine ,Animals ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Ubiquitins ,Organic Chemistry ,Amyotrophic Lateral Sclerosis ,medicine.disease ,Rats ,Disease Models, Animal ,030104 developmental biology ,proteasome ,Proteasome ,Proteasome assembly ,biology.protein ,ALS ,030217 neurology & neurosurgery - Abstract
Proteasomal dysfunction is known to be associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). Our previous reports have shown that a mutant form of ubiquilin-2 (UBQLN2) linked to ALS/FTD leads to neurodegeneration accompanied by accumulations of the proteasome subunit Rpt1 in transgenic rats, but the precise pathogenic mechanisms of how this mutation impairs the proteasome remains to be elucidated. Here, we reveal that this UBQLN2 mutation in rats disrupted the proteasome integrity prior to neurodegeneration, that it dissociated the 26S proteasome in vitro, and that its depletion did not affect 26S proteasome assembly. During both disease progression and in an age-dependent manner, we found that proteasome subunits were translocated to the nucleus, including both of the 20S core particles (PSMA1 and PSMB7) and the 19S regulatory particles (Rpt1 and Rpn1), suggesting that defective proteasome function may result from the proteasome-subunit mislocalization. Taken together, the present data demonstrate that impaired proteasome assembly is an early event in the pathogenesis of UBQLN2-associated neurodegeneration in mutant UBQLN2 rats.
- Published
- 2021