CHMP2Bintron5-expressing cell
TAR DNA-binding protein 43 (TDP-43)-positive cytoplasmic aggregation is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Thus, the aggregations of TDP-43 play an important role in the neurodegeneration of ALS/FTLD. Endosome is a key machinery of membrane trafficking in eukaryote cells and is involved in the autophagy-lysosome pathway. Endosome-related genes such as CHMP2B, Alsin, and TMEM106B are disease-causative genes or genetic modifiers of ALS/FTLD. However, the association between endosomes and TDP-43 aggregations is barely investigated. Intriguingly, the C-terminal truncation mutation of CHMP2B, which causes frontotemporal dementia associated with chromosome 3 (FTD3), disrupts the fusion of late endosomes with lysosomes. Nevertheless, FTD3 does not cause TDP-43 pathology. Herein, we report that late endosome dysfunction induced by the CHMP2B mutant activates the degradation of TDP-43 aggregation. Transcriptome analysis revealed that the overexpression of CHMP2Bintron5 increases the HSP70 expression. To the best of our knowledge, this study first investigated the association between TDP-43 aggregation formation and late endosome membrane trafficking, which provides a novel insight into the disease mechanism of ALS/FTLD.