STUDYING NEURONAL PROTEOSTASIS DURING AGING AND AD WITH NOVEL PROTEIN TAGGING TOOLS - PROJECT SUMMARY A CAU…

Assistance award details

Assistance award identifier

ASST_NON_R00AG088304_075

FAIN

R00AG088304

Recipient

SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$248,476

Period

Aug 8, 2024 – Jul 31, 2029

Fiscal year

2026

Place of performance state

CA

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

STUDYING NEURONAL PROTEOSTASIS DURING AGING AND AD WITH NOVEL PROTEIN TAGGING TOOLS - PROJECT SUMMARY A CAUSAL HALLMARK OF BRAIN AGING AND ALZHEIMER’S DISEASE (AD) IS LOSS OF PROTEOSTASIS, THE MAINTENANCE OF PROTEOME HEALTH THROUGH SEVERAL PROCESSES, INCLUDING PROTIEN DEGRADATION/CLEARANCE (HEREAFTER, ‘TURNOVER’). NEURONAL PROTEOSTASIS IS EXCEPTIONALLY VULNERABLE DURING AGING AND AD AS EVIDENCED BY THE ACCUMULATION OF DYSFUNCTIONAL OR TOXIC NEURONAL PROTEINS, SUCH AS PTAU AND AΒ, CAUSAL FOR NEURON DYSFUNCTION AND DEGENERATION. WHILE THERE IS AN APPRECIATION FOR THE ROLE OF DYSREGULATED PROTEOSTASIS IN BRAIN AGING AND AD, MUCH REMAINS TO BE UNDERSTOOD ABOUT THE DYNAMICS OF NEURONAL PROTEIN TURNOVER (NPT), CONSEQUENCES OF ABERRANT NPT, AND NPT REGULATORS DURING AGING AND AD. I HYPOTHESIZE THAT NPT IS COMPROMISED WITH AGING AND AD, ULTIMATELY WORSENING AGE AND AD PHENOTYPES, AND NPT IS AT LEAST PARTIALLY REGULATED BY LYSOSOMAL BIOLOGY AND MICROGLIA. I AM UNIQUELY POSITIONED TO ADDRESS MY HYPOTHESES THANKS TO MY ESTABLISHMENT OF A NEW IN VIVO MODEL OF BIOORTHOGONAL NON-CANONICAL AMINO ACID TAGGING (BONCAT). BONCAT PERMITS THE TAGGING OF NEWLY SYNTHESIZED PROTEINS WITH AN AZIDE-BEARING PHENYLALANINE (AZF) IN A CELL-SPECIFIC MANNER. TAGGED PROTEINS CAN BE PULLED DOWN AND ANALYZED BY MASS SPECTROMETRY (MS). WHEN AZF IS PROVIDED TO BONCAT MICE IN A PULSE- CHASE ADMINISTRATION SCHEME AND MICE ARE SACRIFICED AT DIFFERENT TIME POINTS IN THE CHASE, TAGGED PROTEINS CAN BE PULLED DOWN AND THEIR REDUCTION OVER THE CHASE/TIME, REPRESENTATIVE OF TURNOVER, CAN BE EXAMINED. I HAVE PERFORMED THIS EXPERIMENT IN YOUNG AND AGED NEURONAL-BONCAT MICE, FINDING >800 RELATIVELY LONGER-LIVED PROTEINS (RLLPS) WITH AGING, MANY OF WHICH ARE IN PATHWAYS OF NEURODEGENERATION. HERE, I PROPOSE TO PERFORM AN IDENTICAL EXPERIMENT IN AD MODELS, COMPARE THE RESULTS TO AGING, AND USE AN IN VITRO HUMAN TRANSDIFFERENTIATED NEURON MODEL IN CONJUNCTION WITH TARGETED PROTEIN DEGRADATION TO DETERMINE THE