# Cell autonomous and non autonomous induction of degeneration in Drosophila

> **NIH NIH R01** · RICE UNIVERSITY · 2022 · $390,253

## Abstract

Project Summary
Degeneration of neurons or muscle are observed in several human pathologies, including Alzheimer's,
Parkinson's and the hereditary spastic paraplegias (HSP) for neuronal degeneration, and disuse atrophy,
cancer cachexia, and sepsis for muscle degeneration. Despite many recent advances, the molecular
mechanism(s) underlying these degenerative processes remain incompletely understood. To generate such
mechanistic insights, the PIs have recently established a Drosophila model for the HSPs. The specific focus is
in atlastin (atl, Spastic Paraplegia Gene 3A), which encodes an ER fusion protein. Based on the previous
observation that atl knockdown in neurons causes progressive, age-dependent locomotor deficits, the we
asked if this knockdown also caused progressive cellular degeneration. Investigations into the adult thoracic
musculature revealed that atl loss from either neuron or muscle caused progressive degeneration associated
with a number of other pathologies including accumulation of aggregates containing ubiquitin, increased
reactive oxygen species (ROS), and activation of the JNK/Foxo stress response pathway. Administering the
drug rapamycin, which inhibits the Tor kinase, or decreasing Tor gene dosage reversed many of these
pathologies at least partially, indicating that atl loss might activate muscle Tor. Muscle Tor and Foxo activation
have also been observed in denervation-induced muscle atrophy. In this application, experiments are proposed
to elucidate the mechanisms by which atl loss causes progressive muscle pathologies. Aim #1 will test the
hypothesis that muscle Tor is activated by atl loss, determine if Tor activity is sufficient as well as necessary for
atl loss phenotypes, and test the prediction that Tor activity promotes muscle degeneration by inhibiting
autophagy. Aim #2 will examine the causal relationship between activated Tor and increased ROS, and
between ROS and the JNK/Foxo stress pathway. In particular, we will test two non-mutually exclusive
hypotheses explaining Foxo activation; first, that activated Tor increases ROS, which in turn is responsible for
JNK activation, and finally Foxo activation, and second, that activated Tor activates its target S6K, which in
turn down-regulates insulin signaling, thus decreasing activity of the Foxo inhibitor Akt. Aim #3 will test the
hypothesis that neuronal atl loss activates muscle Tor by attenuating glutamatergic neuromuscular
transmission. In particular, it will be determined if deletion of one glutamate receptor, previously shown to be
sufficient to activate muscle Tor, will cause similar muscle pathologies as is observed by neuronal atl
knockdown. In addition, it will be determined if neuronal atl loss confers neuronal phenotypes similar to those
conferred by glutamate receptor deletion. Successful completion of these experiments will provide novel and
critical mechanistic insights linking defective synaptic input conferred by atl loss to muscle degeneration. Th...

## Key facts

- **NIH application ID:** 10343843
- **Project number:** 5R01NS102676-05
- **Recipient organization:** RICE UNIVERSITY
- **Principal Investigator:** JAMES A MCNEW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,253
- **Award type:** 5
- **Project period:** 2018-06-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343843

## Citation

> US National Institutes of Health, RePORTER application 10343843, Cell autonomous and non autonomous induction of degeneration in Drosophila (5R01NS102676-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10343843. Licensed CC0.

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