# Genetic Analysis of Neurodegeneration

> **NIH NIH R35** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $894,043

## Abstract

Neurodegenerative diseases are common and devastating disorders, which will become increasingly
prevalent as our population ages. Unfortunately, despite years of effort and some promising leads, we still
do not have disease-modifying therapies. To provide an alternative approach to studying these disorders
and identifying potential therapeutics we have pioneered the use of Drosophila as a model system for
studying neurodegeneration, with a particular emphasis on Parkinson’s disease and Alzheimer’s disease.
Our studies have allowed us to identify genes controlling neurodegeneration in our fly models. We have
subsequently verified these findings in vertebrate models of the diseases, in postmortem brain tissue from
patients and in patient-derived cells. In the current proposal we will capitalize on our prior progress by
exploring in mechanistic detail the role alterations of the spectrin cytoskeleton play in promoting
neurodegeneration in α-synucleinopathies. Specifically, we will test the hypothesis that α-synuclein binds to
the ankyrin-binding domain of ß-spectrin and thereby perturbs autophagosome transport and maturation.
We have recently developed a powerful new model of α-synuclein toxicity in Drosophila. Our previous
model showed striking specificity for dopaminergic neurons. While valuable for exploring toxicity to
dopamine neurons, a very important cell type for Parkinson’s disease, the restricted pathology present
limited implementation of large-scale genetic screens. We have therefore created a model of α-synuclein
neurotoxicity in which age-dependent neurodegeneration is significantly more widespread. Our new model
has facilitated completion of a genome-scale genetic screen, an important strength of Drosophila models.
Importantly, our new α-synucleinopathy model employs a dual transcriptional system we have developed,
which allows simultaneous and independent manipulation of gene expression, at scale, in neurons and glia.
We can now define the broad complement of mechanisms by which glia control toxicity of α-synuclein in
neurons non-cell autonomously. Given the growing evidence for an important role for glia in
neurodegenerative disease, these studies have the potential for significant impact.

## Key facts

- **NIH application ID:** 10835062
- **Project number:** 5R35NS132225-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MEL B FEANY
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $894,043
- **Award type:** 5
- **Project period:** 2023-05-01 → 2031-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10835062

## Citation

> US National Institutes of Health, RePORTER application 10835062, Genetic Analysis of Neurodegeneration (5R35NS132225-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10835062. Licensed CC0.

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