# Mechanisms Underlying Axonopathy in Hereditary Spastic Paraplegia

> **NIH NS R01** · UNIVERSITY OF WISCONSIN-MADISON · 2026 · $375,430

## Abstract

Project Summary
 Axonal degeneration within the corticospinal tract leads to several neurological diseases, including
hereditary spastic paraplegias (HSPs), which are a clinically and genetically heterogeneous group of gait
disorders characterized by poor balance, spasticity, and progressive muscle weakness that can ultimately result
in paralysis. Leveraging parallel animal (rat) and induced pluripotent stem cell (iPSC)-based models, our goal is
to develop a better understanding of the pathomechanisms that underlie neurodegeneration resulting from
mutations in genes that cause HSP, with a longer term goal of using these models as platforms to identify new
therapeutics to combat disease. Using CRISPR-mediated genome editing, we have developed physiologically
relevant models that recapitulate phenotypes exhibited by patients suffering from HSP. Specifically, CRISPR-
modified rats expressing pathological variants of SPG4 (spastin) and SPG57 (TFG) demonstrate early onset
hind limb spasticity and ataxia, which rapidly progresses to hind limb paralysis. Other rat models, including those
harboring a truncation of SPG80 (UBAP1) identified previously in patients, exhibit later onset disease phenotypes,
enabling us to examine disease progression in multiple, unique contexts. We now have an unprecedented
opportunity to determine the mechanistic basis of the axonopathies observed. In particular, we plan to use high-
resolution, live cell confocal imaging and electron tomography to test the hypothesis that changes in the
trafficking of specific factors, including neurofilament proteins implicated previously in neurodegenerative
disease, contribute to impaired neuronal function in HSP. We will also determine how neurofilament trafficking
defects observed relate to disease onset based on a combination of electromyography studies, histopathology,
and comprehensive gait and kinematic analysis of rodent movement as spasticity and muscle weakness ensues.
Furthermore, we will determine

## Key facts

- **NIH application ID:** 11324245
- **Project number:** 5R01NS124165-05
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Anjon  Audhya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NS
- **Fiscal year:** 2026
- **Award amount:** $375,430
- **Award type:** 5
- **Project period:** 2022-05-01T00:00:00 → 2027-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11324245

## Citation

> US National Institutes of Health, RePORTER application 11324245, Mechanisms Underlying Axonopathy in Hereditary Spastic Paraplegia (5R01NS124165-05). Retrieved via AI Analytics 2026-07-11 from https://api.ai-analytics.org/grant/nih/11324245. Licensed CC0.

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