Extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) are hallmark of Alzheimer disease (AD). These aggregates, along with actin-containing inclusions due to abnormalities of actin cytoskeleton induced by amyloid ? (A?), lead to axonal transport defect and thereby, axon degeneration. Vasodilator-stimulated phosphoprotein (VASP) is a processive actin polymerase and its abnormal activation mediates the formation of actin inclusions under pathological condition. TRIM9 brain-specific ubiquitin ligase ubiquitinates and degrades VASP to facilitate axon branching during neural development, suggesting that TRIM9 is a critical brain- specific E3 ubiquitin ligase that controls VASP-mediated axon branch formation and NF-?B- mediated neuroinflammation in normal conditions. As a hyperactive VASP mediates A? aggregate- induced actin inclusion formation and thereby contributes to axon degeneration in AD patients, we hypothesize that TRIM9 E3 ubiquitin ligase interacts with and degrades the hyperactive VASP to inhibit axon degeneration, thereby alleviating AD pathogenesis. To test this hypothesis, we propose to utilize in vitro biochemical approach (Aim 1) and in vivo mouse model (Aim 2). Collectively, this supplemental proposal provides a unique way to extend our understanding role of TRIM9 ubiquitin ligase in AD progression and facilitates the development of therapeutic approach.

Public Health Relevance

Extracellular amyloid ? (A?) plaques and intracellular neurofibrillary tangles (NFTs) are hallmark of Alzheimer disease (AD). The abnormal activation of Vasodilator-stimulated phosphoprotein (VASP) is a processive actin polymerase. As a hyperactive VASP mediates A? aggregate-induced actin inclusion formation and thereby contributes to axon degeneration in AD patients, we hypothesize that TRIM9 E3 ubiquitin ligase interacts with and degrades the hyperactive VASP to inhibit axon degeneration, thereby alleviating AD pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI116585-05S1
Application #
9871994
Study Section
Program Officer
Singleton, Kentner L
Project Start
2019-08-12
Project End
2020-01-31
Budget Start
2019-08-12
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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