The enhanced association between mutant CHMP2B and spastin is a novel pathological link between frontotemporal dementia and hereditary spastic paraplegias.

ABSTRACT: Chromosome 3-linked frontotemporal dementia (FTD3) is caused by a gain-of-function mutation in CHMP2B, resulting in the production of a truncated toxic protein, CHMP2B^Intron5. Loss-of-function mutations in spastin are the most common genetic cause of hereditary spastic paraplegias (HSP). How these proteins might interact with each other to drive pathology remains to be explored. Here we found that spastin binds with greater affinity to CHMP2B^Intron5 than to CHMP2B^WT and colocalizes with CHMP2B^Intron5 in p62-positive aggregates. In cultured cells expressing CHMP2B^Intron5, spastin level in the cytoplasmic soluble fraction is decreased while insoluble spastin level is increased. These pathological features of spastin are validated in brai

SUBMITTER: Chen Y 

PROVIDER: S-EPMC9682730 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature