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- ? and prions in vitro and slow the clearance of amyloid-? 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-?. 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.

Public Health Relevance

Prion diseases are fatal neurodegenerative disorders caused by the misfolding of the cellular prion protein into aggregates that target specific cell types and brain regions. Heparan sulfate (HS) proteoglycans promote the selective internalization and replication of conformationally variable prions (prion strains) in different neural cell types. These studies will help to define the molecular mechanisms of selective cell vulnerability in neurodegenerative diseases and may provide new therapeutic targets based on blocking HS:prion binding.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Career Transition Award (K99)
Project #
1K99AG061251-01A1
Application #
9822877
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Mackiewicz, Miroslaw
Project Start
2019-08-15
Project End
2021-07-31
Budget Start
2019-08-15
Budget End
2020-07-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093