# Genetic Basis of Dorso-Ventral Patterning in the Drosophila Eye

> **NIH NIH R01** · UNIVERSITY OF DAYTON · 2022 · $294,354

## Abstract

Alzheimer's disease (hereafter, AD), a progressive neurodegenerative disorder, is fatal with no effective
cure to date. The neurodegeneration associated with AD also coincides with accumulation of extra-
cellular amyloid-beta 42 (Aß42) plaques and/or intracellular neurofibrillary tangles (NFTs). The amyloid
plaques comprise of extra-cellular deposition of hydrophobic Aß42 polypeptides, and intracellular
aggregation of NFTs comprising of highly phosphorylated microtubule associate protein tau. The
molecular basis for Aß42 plaques accumulation and/or NFT formation mediated neurodegeneration in
AD is poorly understood. Many strategies including model organisms have been devised. Drosophila
melanogaster, fruit fly, with large repository of mutants, array of genetic tools, and similar genetic
makeup to humans also serves as an excellent model for human diseases like AD. Drosophila can be
used for high throughput genome wide-screens, and for testing and screening of therapeutic compounds.
We have established transgenic fly models where we misexpress high levels of human Aß42 or human
hyperphosphorylated tau polypeptides in the retinal neurons of the eye, which exhibits AD like
neuropathology of progressive neuronal death. These stable transgenic lines exhibits Aß42/ tau
mediated cell death in nearly 100% flies at 29oC. Our goal is to employ our Drosophila eye model to (a)
identify and characterize Hippo as a genetic modifier, (b) test if alterations in Hippo activity is correlated
Aß42 and/ or tau mediated neurodegeneration and look for chemical inhibitors of Aß42 plaque/ tau
mediated Alzheimer's neuropathology. In a forward genetic screen, we identified highly conserved
growth regulatory Hippo signaling pathway members as dominant modifier of neurodegeneration caused
by accumulation of Aß42 or hyperphosphorylated tau polypeptides. We will investigate the role of Hippo
signaling pathway in tau and Aß42 plaque mediated neurodegeneration. The role of Hippo signaling has
been extensively studied in growth regulation but its role in neurodegeneration is relatively
underexplored. The second aim is to identify biomarkers and chemical inhibitors of Hippo signaling in
Aβ42 and tau mediated neurodegeneration. We will study molecular mechanisms underlying the genetic
interactions of Hippo pathway components with Aß42 or tau mediated neurodegeneration. We have
established a chemical screen assay using these transgenic flies. We will test the inhibitors of Hippo
signaling pathway for their efficacy to block Aß42and/or tau mediated neurodegeneration. In future, we
will translate these findings from flies to humans using human patient samples. These basic studies are a
prerequisite to exploring and developing therapies for neurodegenerative disorders like AD for which
there are no effective treatments. We can further evaluate these potential drug targets for their diagnostic
or therapeutic value in the detection or treatment of neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10499369
- **Project number:** 3R01EY032959-02S1
- **Recipient organization:** UNIVERSITY OF DAYTON
- **Principal Investigator:** Madhuri Kango-Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $294,354
- **Award type:** 3
- **Project period:** 2021-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499369

## Citation

> US National Institutes of Health, RePORTER application 10499369, Genetic Basis of Dorso-Ventral Patterning in the Drosophila Eye (3R01EY032959-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10499369. Licensed CC0.

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