Graduation Year

2025

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Laura J. Blair, Ph.D.

Committee Member

Danielle Gulick, Ph.D.

Committee Member

Robert Deschenes, Ph.D.

Committee Member

Gopal Thinakaran, Ph.D.

Committee Member

Ioannis Gelis, Ph.D.

Keywords

molecular chaperones, Hsp40, JDP, tauopathies

Abstract

Neurodegenerative diseases often feature the pathological buildup of misfolded proteins, and tau is a principal culprit in multiple tauopathies. One chaperone of emerging interest is DnaJB6b, a member of the Hsp40/DnaJ family, which exhibits potent anti-aggregation activity against several disease-related proteins. Recent investigations highlight its unique capacity to recognize and neutralize aggregation-prone forms of tau. DnaJB6b appears potent against multiple variants of tau and may be acting against tau, in part, by directing misfolded tau toward proteasomal clearance. The first lines of evidence come from systematic chaperone screens, where DnaJB6b repeatedly emerged as a strong suppressor of tau seeding. Further studies revealed that DnaJB6b physically interacts with pathological tau species, stabilizing them in a conformation more amenable to proteolysis. Notably, tau-specific cell lines and induced models showed significant reductions in intracellular tau accumulation when DnaJB6b was overexpressed, implicating this chaperone in the maintenance of neuronal proteostasis under diseased conditions. In vivo, the potential of DnaJB6b as a target for neurodegenerative disease becomes more compelling. In a mouse model known to develop robust tau pathology, elevated DnaJB6b expression alleviated key behavioral deficits, including memory impairments, potentially through reduction of pathology, however biochemical and validation studies are still needed. These findings suggest that DnaJB6b may function as a frontline defense against tau, and other pathological proteins. As the molecular basis of this activity continues to be elucidated, DnaJB6b offers a prospective avenue for disease modification, supporting the broader potential of co-chaperones as therapeutic targets in tauopathies and beyond.

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