# Identification of Presinilin downstream targets in neuronal survival

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $734,120

## Abstract

Alzheimer's disease (AD) is the most common cause of dementia and neurodegeneration, but no
disease-modifying therapy is available. The Presenilin (PSEN) genes harbor ~90% of the mutations linked to
familial AD (FAD), highlighting its importance in AD pathogenesis. These FAD PSEN mutations are mostly
missense mutations (>260) scattered throughout the coding sequence, consistent with a loss-of-function
mechanism. Presenilin (PS) is essential for learning and memory, synaptic function and neuronal survival
during aging, and contains the active site of γ-secretase. Presenilin conditional double knockout (PS cDKO)
mice lacking PS expression in the adult cerebral cortex recapitulate key features of AD, including profound
age-dependent neurodegeneration, gliosis, inflammatory responses and tau hyperphosphorylation. Studies in
C. elegans, Drosophila and cultured mammalian cells showed that FAD mutations impair PS function and γ-
secretase activity. We recently developed two knockin (KI) mice expressing FAD PSEN1 mutations, L435F and
C410Y, and homozygous KI/KI mice show striking resemblance to PS1-/- mice, including perinatal lethality,
abolished γ-secretase activity, impaired neurogenesis and decreased Notch signaling, demonstrating that FAD
mutations resemble the PS1-null mutation in vivo. The molecular mechanism by which PS maintains neuronal
function and survival is unclear. Identification of PS downstream targets and γ-secretase substrates will
not only elucidate the molecular mechanism underlying PS function and dysfunction, but may provide
novel therapeutic targets as well. In the current application, we will take advantage of the power of fly
genetics to identify PS downstream targets and γ-secretase substrates involved in the regulation of neuronal
survival and longevity. Specifically, we will generate conditional mutant flies, in which Presenilin ortholog (Psn)
or Nicastrin ortholog (Nct) are inducibly knocked down by shRNA in adult neurons, and then use these mutant
flies to screen for γ-secretase substrates involved in mediating neuronal survival and lifespan followed by
validation in fly and mouse models (Aim 1). We will also perform whole-genome RNAi-based genetic screens
in Drosophila primary cultured neurons to identify RNAi lines that can correct PS dysfunction, and then validate
the identified genes in fly models for their abilities to restore PS dysfunction (Aim 2). Completion of the
proposed studies will elucidate the molecular pathways by which PS protects neuronal survival during aging
and may provide novel targets that can be further explored for disease-modifying therapy of AD.

## Key facts

- **NIH application ID:** 9896883
- **Project number:** 5R01NS101745-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** NORBERT PERRIMON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $734,120
- **Award type:** 5
- **Project period:** 2017-03-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896883

## Citation

> US National Institutes of Health, RePORTER application 9896883, Identification of Presinilin downstream targets in neuronal survival (5R01NS101745-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896883. Licensed CC0.

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