TY - JOUR
T1 - DJ-1 Molecular Chaperone Activity Depresses Tau Aggregation Propensity through Interaction with Monomers
AU - Jimenez-Harrison, Daniela
AU - Huseby, Carol J.
AU - Hoffman, Claire N.
AU - Sher, Steven
AU - Snyder, Dalton
AU - Seal, Brayden
AU - Yuan, Chunhua
AU - Fu, Hongjun
AU - Wysocki, Vicki
AU - Giorgini, Flaviano
AU - Kuret, Jeff
N1 - Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023/3/7
Y1 - 2023/3/7
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.biochem.2c00581
DO - 10.1021/acs.biochem.2c00581
M3 - Article
C2 - 36813261
AN - SCOPUS:85148772233
SN - 0006-2960
VL - 62
SP - 976
EP - 988
JO - Biochemistry
JF - Biochemistry
IS - 5
ER -