Frontotemporal Dementia Patient Neurons With Progranulin Deficiency Display Protein Dyshomeostasis

Elia, L. P.; Herting, B.; Alijagic, A.; Buselli, C.; Wong, L.; Morrison, G.; Prado, M. A.; Paolo, J. A.; Gygi, S.; Finley, D.; Finkbeiner, S.

doi:10.1101/2023.01.18.524611

bioRxiv · 10.1101/2023.01.18.524611

Frontotemporal Dementia Patient Neurons With Progranulin Deficiency Display Protein Dyshomeostasis

Elia, L. P.·Herting, B.·Alijagic, A.·Buselli, C.·Wong, L.·Morrison, G.·Prado, M. A.·Paolo, J. A.·Gygi, S.·Finley, D.·Finkbeiner, S.

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Abstract

Haploinsufficiency of progranulin (PGRN) causes frontotemporal dementia (FTD), a devastating neurodegenerative disease with no effective treatment. PGRN is required for efficient proteostasis, as loss of neuronal PGRN results in dysfunctional lysosomes and impaired clearance and cytoplasmic aggregation of TDP-43, a protein involved in neurodegeneration in FTD. These and other events lead to neurodegeneration and neuroinflammation. However, the detailed mechanisms leading to protein dyshomeostasis in PGRN-deficient cells remain unclear. We report here the development of human cell models of FTD with PGRN-deficiency to explore the molecular mechanisms underlying proteostasis breakdown and TDP-43 aggregation in FTD. Neurons differentiated from FTD patient induced pluripotent stem cells (iPSCs) have reduced PGRN levels, and the neurons recapitulate key disease features, including impaired lysosomal function, defective TDP-43 turnover and accumulation, neurodegeneration, and death. Proteomic analysis revealed altered levels of proteins linked to the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) in FTD patient neurons, providing new mechanistic insights into the link between PGRN-deficiency and disease pathobiology.

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Elia, L. P., Herting, B., Alijagic, A., Buselli, C., Wong, L., Morrison, G., Prado, M. A., Paolo, J. A., Gygi, S., Finley, D., Finkbeiner, S.. 2023-01-20. Frontotemporal Dementia Patient Neurons With Progranulin Deficiency Display Protein Dyshomeostasis. https://doi.org/10.1101/2023.01.18.524611

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