# Connecting long-lived protein isomerization to lysosomal failure in Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2021 · $535,213

## Abstract

Summary
Alzheimer’s disease (AD) is the most common cause of dementia and affects approximately 50 million
people worldwide. Although significant resources have been invested, successful therapies have yet to
be discovered, suggesting that alternative approaches may be needed. This proposal will investigate a
new idea connecting modifications spontaneously occurring in long-lived proteins to the underlying
causes of AD. These modifications, known as isomerization and epimerization, represent structural
changes that significantly perturb the behavior of affected proteins. These modifications have largely
escaped prior investigation because they have historically been difficult to detect, but recent advances
in technology have enabled their identification and characterization on a larger scale than previously
possible. We will use these methods to fully characterize these modifications in a protein called tau and
the amyloid beta peptide, which are both intricately involved in the progression of AD. We will also
explore the underlying chemistry leading to the formation of isomerization and epimerization and the
rates at which they accrue. Importantly, we hypothesize that these modifications prevent long-lived
proteins from being broken down and recycled in the lysosome. This hypothesis is supported by
preliminary results and, importantly, provides a pathway that could eventually explain the lysosomal
malfunction that is known to occur in AD and is among the earliest observable problems at the cellular
level. We will perform experiments to determine whether any of the lysosomal proteases, the molecules
responsible for degrading proteins, are able to digest the modified proteins. Undigested protein
fragments persisting in the lysosome due to isomerization or epimerization would be subject to
accumulation. This failure closely parallels events occurring with undigested substrates in lysosomal
storage disorders and provides a potential explanation for the previously observed connections
between the two diseases, which exhibit similar pathology. The ultimate goal of this project is to
establish that modifications to long-lived proteins initiate events that ultimately lead to lysosomal failure
in AD, which will open up new therapeutic strategies for exploration.

## Key facts

- **NIH application ID:** 10140258
- **Project number:** 5R01AG066626-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Ryan Roy Julian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $535,213
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140258

## Citation

> US National Institutes of Health, RePORTER application 10140258, Connecting long-lived protein isomerization to lysosomal failure in Alzheimer's disease (5R01AG066626-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10140258. Licensed CC0.

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