Hung, Christy;
Patani, Rickie;
(2023)
Elevated 4R tau contributes to endolysosomal dysfunction and neurodegeneration in VCP-related frontotemporal dementia.
Brain
, Article awad370. 10.1093/brain/awad370.
(In press).
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Abstract
FTD and ALS are two untreatable neurodegenerative diseases that exist on a clinical, genetic, and pathological spectrum. The VCP gene is highly relevant, being directly implicated in both FTD and ALS. Here, we investigate the effects of VCP mutations on the cellular homoeostasis of hiPSC-derived cortical neurons, focusing on endo-lysosomal biology and tau pathology. We find that VCP mutations cause abnormal accumulation of enlarged endo-lysosomes accompanied with impaired interaction between nuclear FUS and SFPQ in human cortical neurons. The spatial dissociation of intra-nuclear FUS and SFPQ correlates with alternative splicing of the MAPT pre-mRNA and increased tau phosphorylation. Importantly, we show that increased 4R tau using antisense oligonucleotide technology is sufficient to drive toxic changes in control human neurons, which phenocopy VCP-mutant neurons. In summary, our findings demonstrate that tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress and apoptosis are driven by a pathogenic increase in 4R tau.
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