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
2015-02-05
Project End
2021-01-31
Budget Start
2019-08-12
Budget End
2021-01-31
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
Seo, Gil Ju; Kim, Charlotte; Shin, Woo-Jin et al. (2018) TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing. Nat Commun 9:613
Liang, Qiming; Wei, Dahai; Chung, Brian et al. (2018) Novel Role of vBcl2 in the Virion Assembly of Kaposi's Sarcoma-Associated Herpesvirus. J Virol 92:
Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2018) Biomarkers and immunoprofiles associated with fetal abnormalities of ZIKV-positive pregnancies. JCI Insight 3:
Lee, Na-Rae; Ban, Junsu; Lee, Noh-Jin et al. (2018) Activation of RIG-I-Mediated Antiviral Signaling Triggers Autophagy Through the MAVS-TRAF6-Beclin-1 Signaling Axis. Front Immunol 9:2096
Gruffaz, Marion; Zhou, Shenghua; Vasan, Karthik et al. (2018) Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi's Sarcoma-Associated Herpesvirus Latent and Lytic Replications. MBio 9:
Zhang, Junjie; Zhao, Jun; Xu, Simin et al. (2018) Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication. Cell Host Microbe 24:234-248.e5
Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2017) Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy. Nat Microbiol 2:1558-1570
Stittrich, Anna B; Ashworth, Justin; Shi, Mude et al. (2016) Genomic architecture of inflammatory bowel disease in five families with multiple affected individuals. Hum Genome Var 3:15060
Seo, Gil Ju; Choi, Younho; Jung, Jae U (2016) No TRIFling Matter on STING. Cell Host Microbe 20:277-278
Liang, Qiming; Luo, Zhifei; Zeng, Jianxiong et al. (2016) Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy. Cell Stem Cell 19:663-671

Showing the most recent 10 out of 21 publications