4R tau drives endolysosomal and autophagy dysfunction in frontotemporal dementia

Abstract

Dysfunction of the neuronal endolysosome and macroautophagy/autophagy pathway is emerging as an important pathogenic mechanism in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The <i>VCP</i> (valosin-containing protein) gene is of significant relevance, directly implicated in both FTD and ALS. In our recent study, we used patient-derived stem cells to study the effects of <i>VCP</i> mutations on the endolysosome and autophagy system in human cortical excitatory neurons. We found that <i>VCP</i> mutations cause an abnormal accumulation of enlarged endosomes and lysosomes, accompanied by reduced autophagy flux. <i>VCP</i> mutations also lead to the spatial dissociation of intra-nuclear RNA-binding proteins, FUS and SFPQ, which correlates with alternative splicing of the <i>MAPT</i> pre-mRNA and increased tau phosphorylation. Importantly, we found that an increase in the 4R-tau isoform is sufficient to drive toxic changes in healthy human cortical excitatory neurons, including tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress, and apoptosis. Together, our data suggest that endolysosomal and autophagy dysfunction could represent a convergent pathogenic "design principle" shared by both FTD and ALS.