{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Samelson AJ"],"funding":["NIBIB NIH HHS","NIA NIH HHS","NIAID NIH HHS","NCI NIH HHS","NINDS NIH HHS"],"pubmed_abstract":["Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation and subsequent dysfunction and death, but the underlying mechanisms 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. We discover that the E3 ubiquitin ligase CUL5<sup>SOCS4</sup> is a potent modifier of tau levels in human neurons, ubiquitinates tau, and is a correlated with vulnerability to tauopathies in mouse and human. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, which generates tau proteolytic fragments like those in disease and changes tau aggregation <i>in vitro</i>. These results reveal new principles of tau proteostasis in human neurons and pinpoint potential therapeutic targets for tauopathies."],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2023.06.16.545386"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10312804"],"repository":["biostudies-literature"],"pubmed_title":["CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis."],"pmcid":["PMC10312804"],"funding_grant_id":["K99 AG080116","P30 CA082103","F32 AG076281","R01 AG082141","U24 AG072458","U54 AI170792","U19 AG060909","R01 AG062359","U54 NS100717","U54 NS123746","T32 EB009383","F32 AG063487"],"pubmed_authors":["Rohanitazangi G","Bose R","Travaglini KJ","Lawrence RE","McKetney J","Kampmann M","Goodness D","Kanaan NM","Dixon G","Gross JD","Jin J","Tse E","Ariqat N","Abskharon R","Lam VL","Bravo CP","Carroll EC","Pan H","Eisenberg D","Marzette E","Gestwicki JE","Gan L","Swaney DL","Tian R","Southworth DR","Samelson AJ"],"additional_accession":[]},"is_claimable":false,"name":"CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.","description":"Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation and subsequent dysfunction and death, but the underlying mechanisms 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. We discover that the E3 ubiquitin ligase CUL5<sup>SOCS4</sup> is a potent modifier of tau levels in human neurons, ubiquitinates tau, and is a correlated with vulnerability to tauopathies in mouse and human. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, which generates tau proteolytic fragments like those in disease and changes tau aggregation <i>in vitro</i>. These results reveal new principles of tau proteostasis in human neurons and pinpoint potential therapeutic targets for tauopathies.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Nov","modification":"2026-06-18T03:08:40.412Z","creation":"2025-09-01T03:07:45.663Z"},"accession":"S-EPMC10312804","cross_references":{"pubmed":["37398204"],"doi":["10.1101/2023.06.16.545386"]}}