FUNCTIONAL CHARACTERIZATION OF TAU MUTATION AND POST-TRANSLATIONAL MODIFICATIONS - PROJECT SUMMARY (SEE INS…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
Assistance award details
- Assistance award identifier
- ASST_NON_R00AG080116_075
- FAIN
- R00AG080116
- Recipient
- UNIVERSITY OF CALIFORNIA, LOS ANGELES
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $486,678
- Period
- Apr 15, 2023 – Mar 31, 2028
- Fiscal year
- 2025
- Place of performance state
- CA
- Source file
- FY2025_All_Assistance_Full_20261006.zip
Description
FUNCTIONAL CHARACTERIZATION OF TAU MUTATION AND POST-TRANSLATIONAL MODIFICATIONS - PROJECT SUMMARY (SEE INSTRUCTIONS): PROTEIN AGGREGATION IS A HALLMARK OF NEURODEGENERATIVE DISEASES, INCLUDING ALZHEIMER'S DISEASE, AND THESE DISEASES LACK EFFECTIVE THERAPEUTICS. WE CURRENTLY LACK AN UNDERSTANDING OF THE MOLECULAR AND CELLULAR MECHANISMS CONTROLLING PROTEIN AGGREGATION IN THE HUMAN BRAIN, WHICH WOULD ENABLE NEW THERAPEUTIC STRATEGIES. THE PROTEIN TAU AGGREGATES IN THE BRAIN IN MANY NEURODEGENERATIVE DISEASES CALLED TAUOPATHIES, INCLUDING ALZHEIMER'S DISEASE. IN EARLY STAGES OF DISEASE, TAU AGGREGATES ONLY IN SPECIFIC NEURONS DESPITE BEING EXPRESSED IN EVERY NEURON IN THE BRAIN, IMPLYING THAT SPECIFIC FACTORS IN THE CELLULAR ENVIRONMENT PREDISPOSE TAU TO AGGREGATION. SIMILARLY, TAU MUTATIONS ARE ASSOCIATED WITH THE ONSET OF ONLY SPECIFIC TAUOPATHIES. TOGETHER, THESE DISEASE FEATURES IMPLY THAT TAU IS EXQUISITELY SENSITIVE TO BOTH ITS SEQUENCE PROPERTIES AND ITS CELLULAR ENVIRONMENT. POST-TRANSLATIONAL MODIFICATIONS (PTM) ARE A MECHANISM BY WHICH THE CELLULAR ENVIRONMENT CAN ACT ON A PROTEIN PRIMARY SEQUENCE, SIMILAR TO MUTATION. TAU IS HEAVILY POST-TRANSLATIONALLY MODIFIED AND CHANGES TO TAU PTMS ARE CORRELATED WITH PROGRESSION OF DISEASE. TAU PHOSPHORYLATION AND PROTEOLYSIS ARE PROPOSED TO BE CENTRAL EVENTS IN THE ONSET AND PROGRESSION OF TAUOPATHIES. SIMILARLY, MUTATIONS ARE CORRELATED WITH EARLY DISEASE ONSET AND ARE KNOWN TO HASTEN IN VITRO TAU AGGREGATION. MUTATIONS CAN ALSO CAUSE CHANGES IN PTMS BY CHANGING TAU INTERACTION PARTNERS. THE FUNCTION AND CAUSALITY OF THESE CHANGES TO TAU AGGREGATION, HOWEVER, IS UNKNOWN. I HYPOTHESIZE THAT PTMS AND MUTATIONS LICENSE TAU TO ACCESS SPECIFIC CONFORMATIONS TO FORM AGGREGATES. THE GOAL OF THIS PROPOSAL IS TO COMPREHENSIVELY IDENTIFY (1) THE BIOLOGICAL BASIS OF TAU PTM CHANGES AND (2) HOW TAU MUTATION AND PTMS CAUSE AGGREGATION. I HAVE SHOWN THAT MITOCHONDRIAL ELECTRON TRANSPORT CHAIN DYSFUNCTION CAUSES REMODELING OF TAU P