Endolysosomal dysfunction impairs proteostasis and induces neurodegeneration in vivo.

Transactive response (TAR) DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of the frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) spectrum. Dysfunction of the endolysosomal system, which plays a crucial role in protein trafficking and maintaining proteostasis, has been implicated in FTD-ALS pathogenesis. While the impact of endolysosomal dysfunction on TDP-43 pathology remains unclear, we demonstrated that disrupting the endolysosomal pathway by expressing the constitutively active endosomal protein, Rab5(Q79L), induces TDP-43 aggregation in cultured cells. Here, we generated a mouse model expressing GFP-tagged Rab5(Q79L), demonstrating that GFP-Rab5(Q79L) mice exhibit early motor deficits and endolysosomal dysfunction, including enlarged endosomes, abnormal lysosome morphology, and p62- or ubiquitin-positive inclusions. These mice also developed significant neuronal loss, neuroinflammation, phosphorylated TDP-43 (pTDP-43) inclusions, and nuclear envelope and nuclear pore structural defects reminiscent of FTD-ALS. Accordingly, GFP-Rab5(Q79L) mice will prove useful in expanding our understanding of endolysosomal dysfunction in proteostasis and pTDP-43 pathology.