# Mechanistic analysis of microtubule dynamics and stability in neurons

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $335,479

## Abstract

PROJECT SUMMARY/ABSTRACT
Communication between neurons and their targets depends on proper synaptic growth and activity. The
microtubule cytoskeleton plays a central role in synaptic terminal development, and microtubule dysfunction is
associated with many neurological disorders. Neurons contain stable and dynamic microtubules, and these two
populations must be properly balanced for synapses to grow and form stable connections. In this proposal, we
use a synergistic combination of in vivo genetic analyses and cell-free in vitro biophysical approaches to
elucidate the mechanisms by which microtubule dynamics and stability are balanced. We leverage a novel α-
tubulin mutant that alters the normal microtubule balance and perturbs synaptic growth. This tubulin mutation
disrupts a highly conserved, essential α-tubulin site that is acetylated. Post-translational modifications (PTMs),
such as acetylation, have the potential to directly and specifically regulate microtubule stability and dynamics to
shape synaptic morphogenesis, yet relatively few microtubule PTMs have been studied. Our preliminary data
implicate this previously uncharacterized α-tubulin site in regulating the addition of tubulin dimers to growing
microtubule ends, which suggests a novel acetylation-based mechanism to control microtubule dynamics.
Based on our preliminary findings, we will test the hypothesis that microtubule dynamics and stability are
balanced by α-tubulin acetylation and other known regulators to shape synaptic terminal morphogenesis (Aim
1). We will use the Drosophila neuromuscular junction as a model and investigate the effects of manipulating
microtubule dynamics and stability on two different motor neuron types, called type Ib and type Is, whose
synaptic terminals have distinct morphologies and transmission properties. Our preliminary data indicate that
altering the microtubule cytoskeleton has strikingly different effects on the growth of type Ib and Is synaptic
terminals. We will test the hypothesis that stable and dynamic microtubules are uniquely balanced in different
neuron types to establish distinct neuron-specific synaptic structures and activities (Aim 2). Combined, our
studies will reveal novel mechanisms that regulate synaptic microtubule networks and provide fundamental
new insight into the central role that microtubules play in creating diverse synaptic morphologies and functions.

## Key facts

- **NIH application ID:** 10536622
- **Project number:** 5R01NS116373-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** JILL C WILDONGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $335,479
- **Award type:** 5
- **Project period:** 2020-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536622

## Citation

> US National Institutes of Health, RePORTER application 10536622, Mechanistic analysis of microtubule dynamics and stability in neurons (5R01NS116373-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10536622. Licensed CC0.

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