# Presenilin 1 Modulates Lysosome Function and Tau Degradation

> **NIH NIH F30** · UNIVERSITY OF ROCHESTER · 2021 · $51,036

## Abstract

A common feature of Alzheimer’s disease (AD), as well as other older age onset neurodegenerative diseases,
is the accumulation of misfolded, abnormally modified proteins. In AD, aggregates of tau are a classical
hallmark. A significant contributing factor to the formation of these proteinaceous accumulations is dysfunction
of the lysosome-dependent degradative pathways. Interestingly, the majority of autosomal dominant familial
AD (FAD) cases are caused by mutations in presenilin 1 (PS1), the catalytic subunit of the  secretase
complex, which also likely facilitates lysosomal function. However, the role of PS1 in mediating lysosome
biology and the clearance of tau has not been fully delineated. Given previous studies and our preliminary
data, the UNDERLYING PREMISE of this proposal is that in neurons PS1 plays a fundamental role in
regulating the function of lysosomes and, thus, tau turnover. Lysosomes play a key role in maintaining
proteostasis as multiple degradative pathways direct their cargos to the lysosome for degradation/recycling.
Alterations in the activity or intracellular localization of lysosomes contribute to the pathogenic processes of
these neurodegenerative diseases. Given the importance of lysosome function to neuron health,
understanding how PS1 impacts lysosome biology is of high importance. CRITICAL KNOWLEDGE GAPS
include: how depletion of PS1 in primary neurons impacts lysosome pH, the effects of PS1 depletion on
autophagosome-lysosome and endosome-lysosome fusion, the impact of PS1 depletion on tau turnover and
how re-acidification of lysosomes in neurons with PS1 depleted affects the PS1-induced lysosomal fusion
defects and deficiencies in tau turnover. Considering these critical knowledge gaps the OVERALL
HYPOTHESIS is that depletion of PS1 leads to impairment of lysosome function, localization and fusion
events, which negatively impact tau clearance. In the context of this overall hypothesis, the specific aims of this
proposal are to test the hypotheses: (1) that PS1 plays a role in the acidification, activity, and localization of
lysosomes and other degradative vesicles within different neuronal compartments and (2) that vesicle-
mediated processing/clearance and intraneuronal localization of tau is impaired by knockdown of PS1. These
studies will be carried out using primary rat cortical neuron cultures. Overall this a transformative project that
addresses significant gaps in our scientific knowledge. The proposal is innovative in conceptualizing PS1 as a
key regulator of lysosome function and thus a significant contributor to proteostasis in general and tau more
specifically. Further, technically it is innovative as we will be using an optogenetically driven proton pump to
decrease the pH of lysosomes after PS1 knockdown to determine if maintaining an acidified lysosome is
sufficient to restore its function. The IMPACT of these studies will be a significant contribution to our
understanding of the role of PS1 in regu...

## Key facts

- **NIH application ID:** 10368913
- **Project number:** 5F30AG067628-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Carol Ann Deaton
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368913

## Citation

> US National Institutes of Health, RePORTER application 10368913, Presenilin 1 Modulates Lysosome Function and Tau Degradation (5F30AG067628-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10368913. Licensed CC0.

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