The accumulation of aggregated tau protein in the brain is a defining feature of Alzheimer?s disease (AD) and a logical therapeutic target to prevent AD progression. Genetic evidence in mice strongly supports the notion that tau promotes cognitive deficits in AD. While anti-aggregation and immunotherapy approaches have emerged as potential strategies to reduce tau aggregation in the brain, these target late-stage tau intermediates. Much less is known about the early-stage events that give rise to tau aggregates in otherwise healthy neurons, a time period in which chaperone-dependent refolding acts in a compensatory manner to restore tau function as a critical microtubule (MT) stabilizing factor. We seek to define these early-stage tau triage decisions since clinically targeting tau in this earlier window is highly desirable to prevent tau accumulation, particularly in asymptomatic individuals years to decades from disease onset. The C-terminus of heat shock 70-interacting protein (or CHIP) plays a central role in orchestrating protein quality control. While most prior studies have pointed to CHIP?s E3 ligase activity as a principal mediator of client substrate degradation including tau, studies now indicate that CHIP contains a poorly understood intrinsic chaperone function that operates completely independent of its E3 ligase activity. Genetic studies of spinocerebellar ataxia 16 (SCAR 16) patients, a rare neurodegenerative disorder, showed that loss of CHIP co-chaperone activity alone is sufficient to cause neurodegeneration and cognitive dysfunction. These prior studies, combined with our compelling new preliminary data showing that CHIP directly binds and chaperones tau to facilitate its dephosphorylation, provide strong support for a new model of CHIP-mediated tau triage. We hypothesize that CHIP prevents aberrant tau modifications and aggregation, restores normal tau function and MT stabilization, and ameliorates AD-related cognitive decline.
In Aim -1, we will dissect CHIP?s dual functions as a regulator of tau function and phosphorylation using biochemical and biophysical assays in vitro. These studies will provide new mechanistic insights into how CHIP targets and repairs abnormal tau species.
In Aim -2, we will explore a novel role for CHIP in mediating neuroprotection via the stabilization of MTs. We will test the requirements for CHIP co-chaperone activity in maintaining MT integrity and hence promoting survival in neurons that would otherwise undergo degeneration. Finally, in Aim-3, we will test the clinical implications of CHIP co-chaperone function in restoring cognition in an animal model of AD. Overall, our proposal is significant because it will illuminate the early-stage events that determine how tau is initially processed and triaged. It is also innovative because it is the first to highlight dual molecular functions of CHIP that are relevant to tau pathogenesis and the progression of this devastating disease.

Public Health Relevance

Aggregated tau protein is firmly linked to cognitive dysfunction in Alzheimer?s disease (AD) patients. The proposed study will define the critical events that occur during early-stage tau triage, a time period during which aberrant tau aggregation is opposed by a neuroprotective, compensatory response that involves the proteostasis factor C-terminus of Hsc70-interacting protein, or CHIP. The results of this study could provide a new framework to better understand and target aberrant tau species in order to alleviate tau-mediated neurodegeneration in AD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG061188-02
Application #
9876969
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2019-03-01
Project End
2023-12-31
Budget Start
2020-02-01
Budget End
2020-12-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Neurology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599