# Role of heparan sulfate in neural cell vulnerability to prions

> **NIH NIH R00** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $249,000

## Abstract

PROJECT SUMMARY / ABSTRACT
 A major unresolved question in neurodegenerative disease is the mechanisms that drive selective cell
vulnerability. Heparan sulfate proteoglycans (HSPGs) are glycoproteins that promote oligomerization of amyloid-
β and prions in vitro and slow the clearance of amyloid-β in the brain of an Alzheimer’s disease mouse model.
HSPGs interact with misfolded proteins through their HS chains and promote their internalization in immortalized
neural cells. This protein aggregate uptake is profoundly impacted by the HS length and level of sulfation which,
importantly, broadly differ between cell types. We and others have used highly sulfated HS-like glycopolymers
to test the crucial role of HS in the interaction and in vitro replication of prions. However, the composition of
endogenous HS and their specific roles in healthy aged and disease-affected brain are unknown. I found that
mice expressing shorter HS chains showed prolonged survival and profoundly altered prion plaque distribution
in brain when infected with a plaque-forming prion strain, but did not show any change in the prion disease
phenotype caused by aggregate-forming prions. Here I will define the HS molecules that bind to physiological
and misfolded prion protein in different neuronal populations. I hypothesize that the interaction of HS with
misfolded prions is a major determinant underlying the selective cell vulnerability in prion disease. In
Aim 1, I will determine the role of HS sulfation in the prion replication i) in vitro, using HS isolated from distinct
neuronal populations, and ii) in vivo, by mouse models deficient in HS sulfation. I will measure how the variation
in the HS sulfation impacts the PrP cell tropism and lesion targets in the brain, and how age affects HS
composition. I will next manipulate the HS composition in different neuronal populations i) to measure the
selective cell uptake of prions strains and their degree of dependence on HS (Aim 2), and ii) to test a new strategy
to block prion progression based on using HSPG mimetics as vehicles to promote prion degradation in
lysosomes (Aim 3). I expect to define the molecular mechanisms underlying selective cell vulnerability in prion
disease and to discover new targets for the rational design of neuroprotective therapies for patients with prion
disease. Due to the many commonalities between the pathogenesis of prion disease and Alzheimer’s disease, I
plan to ultimately extend my research strategy to the study of cell targeting by amyloid-β. This K99/R00
application is an ideal pathway to independence that is supported by an outstanding group of mentors and
advisors, extensive training in highly innovative techniques, a world-class scientific environment, and clear
departmental commitment.

## Key facts

- **NIH application ID:** 10891672
- **Project number:** 5R00AG061251-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Patricia Aguilar Calvo
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2022-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891672

## Citation

> US National Institutes of Health, RePORTER application 10891672, Role of heparan sulfate in neural cell vulnerability to prions (5R00AG061251-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10891672. Licensed CC0.

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