VCP increases or decreases tau seeding using specific cofactors.

Autor:	Batra S; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX., Vaquer-Alicea J 3rd; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX., Manon VA; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX., Kashmer OM; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX., Lemoff A; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX., Cairns NJ; Department of Clinical and Biological Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom., White CL 3rd; Department of Pathology, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX., Diamond MI; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX.; Department of Neurology, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Aug 30. Date of Electronic Publication: 2023 Aug 30.
DOI:	10.1101/2023.08.30.555637
Abstrakt:	Background: Neurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to an adjacent or connected cell, and serves as a specific template for its own replication in the cytoplasm. In vitro seeding reactions typically take days, yet seeding into the complex cytoplasmic milieu can happen within hours. A cellular machinery might regulate this process, but potential players are unknown. Methods: We used proximity labeling to identify factors that control seed amplification. We fused split-APEX2 to the C-terminus of tau repeat domain (RD) to reconstitute peroxidase activity upon seeded intracellular tau aggregation. We identified valosin containing protein (VCP/p97) 5h after seeding. Mutations in VCP underlie two neurodegenerative diseases, multisystem proteinopathy and vacuolar tauopathy, but its mechanistic role is unclear. We utilized tau biosensors, a cellular model for tau aggregation, to study the effects of VCP on tau seeding. Results: VCP knockdown reduced tau seeding. However, distinct chemical inhibitors of VCP and the proteasome had opposing effects on aggregation, but only when given <8h of seed exposure. ML-240 increased seeding efficiency ~40x, whereas NMS-873 decreased seeding efficiency by 50%, and MG132 increased seeding ~10x. We screened VCP co-factors in HEK293 biosensor cells by genetic knockout or knockdown. Reduction of ATXN3, NSFL1C, UBE4B, NGLY1, and OTUB1 decreased tau seeding, as did NPLOC4, which also uniquely increased soluble tau levels. Reduction of FAF2 and UBXN6 increased tau seeding. Conclusions: VCP uses distinct cofactors to determine seed replication efficiency, consistent with a dedicated cytoplasmic processing complex that directs seeds towards dissolution vs. amplification. Competing Interests: Competing Interests The authors declare no competing interests.
Databáze:	MEDLINE
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