# Uncover the role of glia-neuron crosstalk in hereditary spastic paraplegias

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $375,765

## Abstract

SUMMARY
Hereditary spastic paraplegia (HSP) is a large heterogeneous group of neurogenetic disorders caused
by the length-dependent degeneration of cortical motor neuron axons. Cortical motor neurons, a group
of projection neurons located in motor cortex, control muscle movement through lower motor neurons in
the brain stem and spinal cord. Degeneration of these neurons interrupts the signal transmission from
brain to spinal cord and then muscles, resulting in progressive spasticity and weakness in muscles.
Currently, there remains a lack of effective treatment to ameliorate, stop, or reverse axonal defects in
HSPs. Recent studies show that several HSP proteins can regulate the size of lipid droplets, implying
their roles in lipid metabolisms. Glial cells play an important for generating and regulating lipid
metabolism in the brain. However, whether lipid metabolism is altered in HSP brain and what role glial
cells play in the pathogenesis of HSP are largely unknown. The goal of this proposed study is to dissect
the novel role of lipid metabolism and the interplay between glial cells and neurons in the pathogenesis
of HSP using co-cultures of cortical neurons and glial cells derived from iPSCs of SPG3A patients.
SPG3A is the most common early-onset form of HSP caused by mutations in the ATL-1 gene that
encodes atlastin-1 protein. We will test our hypotheses by pursuing the following three aims: 1) to
identify the contribution of glial cells to axonal and synaptic defects in SPG3A, 2) to determine the role
of glial cells in impaired cholesterol homeostasis in SPG3A, and 3) to rescue axonal and synaptic
defects in SPG3A by targeting the impaired glia-neuron interaction. By comparing co-cultures of cortical
neurons with normal or SPG3A glial cells, our study will provide insights into the role of glial cells in
HSP. The cause-effect relationship between atlastin-1 mutations and axonal phenotypes will be
confirmed by rescuing the mutations in SPG3A iPSCs and by knocking in mutations to normal human
pluripotent stem cells. Moreover, rescue experiments will be performed to identify potential approaches
for mitigating axonal and synaptic defects in HSP through regulating lipid metabolism in glial cells.
Together, our study is expected to reveal novel roles of glial cells in the pathogenesis of HSP and
identify new targets for therapeutic intervention in HSP.

## Key facts

- **NIH application ID:** 10035171
- **Project number:** 1R01NS118066-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** XUE-JUN LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,765
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10035171

## Citation

> US National Institutes of Health, RePORTER application 10035171, Uncover the role of glia-neuron crosstalk in hereditary spastic paraplegias (1R01NS118066-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10035171. Licensed CC0.

---

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