CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.

TitleCRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.
Publication TypeJournal Article
Year of Publication2023
AuthorsSamelson AJ, Ariqat N, McKetney J, Rohanitazangi G, Bravo CParra, Goodness D, Tian R, Grosjean P, Abskharon R, Eisenberg D, Kanaan NM, Gan L, Condello C, Swaney DL, Kampmann M
JournalbioRxiv
Date Published2023 Jun 26
Abstract

A hallmark of age-associated neurodegenerative diseases is the aggregation of proteins. Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to the accumulation of tau aggregates, and subsequent dysfunction and death. The mechanisms underlying cell type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi-based modifier screen in iPSC-derived neurons. The screen uncovered expected pathways, including autophagy, but also unexpected pathways including UFMylation and GPI anchor synthesis, that control tau oligomer levels. We identify the E3 ubiquitin ligase CUL5 as a tau interactor and potent modifier of tau levels. In addition, disruption of mitochondrial function increases tau oligomer levels and promotes proteasomal misprocessing of tau. These results reveal new principles of tau proteostasis in human neurons and pinpoint potential therapeutic targets for tauopathies.

DOI10.1101/2023.06.16.545386
Alternate JournalbioRxiv
PubMed ID37398204
PubMed Central IDPMC10312804
Grant ListU54 NS123746 / NS / NINDS NIH HHS / United States
T32 EB009383 / EB / NIBIB NIH HHS / United States
P30 CA082103 / CA / NCI NIH HHS / United States
K99 AG080116 / AG / NIA NIH HHS / United States
U24 AG072458 / AG / NIA NIH HHS / United States
R01 AG082141 / AG / NIA NIH HHS / United States
U54 NS100717 / NS / NINDS NIH HHS / United States
F32 AG063487 / AG / NIA NIH HHS / United States
R01 AG062359 / AG / NIA NIH HHS / United States