# Microtubule Severing and Regrowth by Spastin

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $322,783

## Abstract

PROJECT SUMMARY Microtubule Severing and Regrowth by Spastin
Hereditary spastic paraplegia (HSP) is a neurodegenerative disease that causes progressive gait
disorder. The most commonly mutated gene found in HSP patients encodes the microtubule-
severing enzyme spastin, which can sever microtubule polymers into shorter fragments. While
microtubule severing proteins—spastin, katanin and fidgetin—have been long thought to
disassemble the cellular microtubule network, in vivo studies in various organisms have shown
that they can actually increase the number of microtubules in cells. Our long-term goal is to
establish a framework for how spastin regulates cellular microtubule networks, and how
perturbation of spastin activity leads to neuronal degeneration.
 Recently, by reconstituting the activity of purified spastin, we discovered that the protein
possesses a novel activity that promotes the regrowth of severed microtubules. This activity is
independent of its canonical severing activity. We showed that the combination of severing and
microtubule regrowth promotion can lead to an exponential increase in the number of
microtubules and the amount of tubulin polymer. Based on this work, we hypothesize that spastin
increases the amount of cellular microtubules by combining these two activities. How spastin
perform these functions, however, is poorly understood.
 The overall objective of this project is to understand the molecular mechanisms of severing
and regrowth using a combination of single-molecule fluorescence microscopy, force
spectroscopy and mathematical modelling. Our two specific aims are: (i) dissect the molecular
mechanics of spastin-dependent microtubule severing, and (ii) test competing models for how
spastin promotes microtubule regrowth. Completion of these aims is expected to yield detailed
kinetic and mechanical mechanisms for spastin’s activities and to generate reagents that will
facilitate future structural and cellular studies, including on the pathophysiology of spastin.

## Key facts

- **NIH application ID:** 10072596
- **Project number:** 1R01GM139337-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jonathon Howard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,783
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072596

## Citation

> US National Institutes of Health, RePORTER application 10072596, Microtubule Severing and Regrowth by Spastin (1R01GM139337-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072596. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*