DJ-1 Molecular Chaperone Activity Depresses Tau Aggregation Propensity through Interaction with Monomers

Daniela Jimenez-Harrison, Carol J. Huseby, Claire N. Hoffman, Steven Sher, Dalton Snyder, Brayden Seal, Chunhua Yuan, Hongjun Fu, Vicki Wysocki, Flaviano Giorgini, Jeff Kuret

Research output: Contribution to journalArticlepeer-review


Tau aggregate-bearing lesions are pathological markers and potential mediators of tauopathic neurodegenerative diseases, including Alzheimer’s disease. The molecular chaperone DJ-1 colocalizes with tau pathology in these disorders, but it has been unclear what functional link exists between them. In this study, we examined the consequences of tau/DJ-1 interaction as isolated proteins in vitro. When added to full-length 2N4R tau under aggregation-promoting conditions, DJ-1 inhibited both the rate and extent of filament formation in a concentration-dependent manner. Inhibitory activity was low affinity, did not require ATP, and was not affected by substituting oxidation incompetent missense mutation C106A for wild-type DJ-1. In contrast, missense mutations previously linked to familial Parkinson’s disease and loss of α-synuclein chaperone activity, M26I and E64D, displayed diminished tau chaperone activity relative to wild-type DJ-1. Although DJ-1 directly bound the isolated microtubule-binding repeat region of tau protein, exposure of preformed tau seeds to DJ-1 did not diminish seeding activity in a biosensor cell model. These data reveal DJ-1 to be a holdase chaperone capable of engaging tau as a client in addition to α-synuclein. Our findings support a role for DJ-1 as part of an endogenous defense against the aggregation of these intrinsically disordered proteins.

Original languageEnglish (US)
Pages (from-to)976-988
Number of pages13
Issue number5
StatePublished - Mar 7 2023

ASJC Scopus subject areas

  • Biochemistry


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