# Identifying common pathomechanisms underlying genetically diverse Hereditary Spastic Paraplegias

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $426,875

## Abstract

Project Summary
Hereditary Spastic Paraplegias (HSPs) represent a heterogeneous group of neurodegenerative disorders that
result in lower limb spasticity and weakness. Mutations that affect more than 80 unique proteins, which function
in disparate cellular processes, have been linked to these debilitating neuropathies. Our goal is to understand
how seemingly unrelated mutations underlying HSPs can result in highly similar clinical outcomes. To address
this issue, we have created a series of pre-clinical rat models of HSP, based on pathological mutations identified
in patients that are believed to regulate distinct cellular processes. We are now uniquely poised to make headway
in defining disease etiology, having demonstrated recently that several of our rat models recapitulate human
disease phenotypes much more accurately as compared to previously established murine models. In particular,
preliminary studies using a subset of our rat models have revealed progressive loss of hind limb function,
spasticity, cortical atrophy, and thinning of the corpus callosum, phenotypes typically associated with HSP in
humans. In this proposal, we will investigate disease onset and progression in multiple genetic contexts to identify
commonalities across multiple HSPs and define early hallmarks of disease. Although HSP-related genes function
in different cellular processes, we hypothesize that dysregulation of specific cellular stress pathways, including
the unfolded protein response represent a unifying feature of HSP progression. We plan to quantitatively assess
unfolded protein response activation in each of our animal models from birth to disease onset and subsequently
throughout disease progression. Additionally, we will leverage an unbiased proteomic examination of
cerebrospinal fluid collected from our animals at various timepoints during disease progression to identify
potential biomarkers that are common to multiple forms of HSP. Together these studies will further our
understanding of the pathomechanisms of neurodegeneration underlying HSP and potentially reveal therapeutic
targets, which will facilitate the identification of treatments that are broadly efficacious across the HSP disease
spectrum.

## Key facts

- **NIH application ID:** 10140983
- **Project number:** 1R21NS120386-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Anjon Audhya
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $426,875
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140983

## Citation

> US National Institutes of Health, RePORTER application 10140983, Identifying common pathomechanisms underlying genetically diverse Hereditary Spastic Paraplegias (1R21NS120386-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10140983. Licensed CC0.

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