Alpha-synuclein (?syn) is a neuron-specific protein known to cause Parkinson?s disease. The protein is always expressed and recent work has shown that ?syn mis-folds into fibrils in peripheral neurons in the gastrointestinal track and the olfactory bulb. These fibrils then spread to the central nervous system in select individuals resulting in neurodegenerative diseases like Parkinson?s disease or Diffuse Lewy Body Dementia. Veteran populations are at risk for developing neurodegenerative diseases as they age and work to understand the cause of Parkinson?s disease will yield new approaches to treat and prevent neurodegenerative diseases. We have discovered that virus infections initiate post-translational modifications of ?syn that are associated with Parkinson?s disease. Moreover, our prior work has shown that ?syn functions to inhibit virus infections from spreading from the peripheral nerves to the central nervous system. Taken together, our findings reveal a stunning new understanding of the role of ?syn in the brain. We hypothesize that viral infections induce post-translational modifications in ?syn as an antiviral mechanism. While this response is acutely protective, exposure increases the risk of ?syn-induced pathology that can result in long term neurodegenerative diseases found in Parkinson?s disease. We will evaluate our hypothesis by defining the mechanism of ?syn-induced inhibition of WNV infection in neurons and defining the interactions between ?syn post-translational modifications and ?-syn fibril spread. We will utilize techniques in molecular virology in combination with established mouse models in the field of Parkinson?s research to define the specific interactions and consequences of the interactions between ?syn and viral infection in the brain. If the proposed studies are completed as outlined, we will provide novel data that will have significant impact on the field of Parkinson?s disease research and neurovirology. Thus, our proposed work will have significant benefits for our veteran populations by improving health and providing potential new approaches to prevent and treat neurodegenerative processes like Parkinson?s disease.

Public Health Relevance

This research proposal will study a protein found in the brain called alpha-synuclein. Alpha-synuclein is known to cause Parkinson?s disease, but how the protein causes disease is not known. Our laboratory discovered that alpha-synuclein inhibits viral infections in the brain, and we discovered that viral infections cause alpha- synuclein to convert to the toxic form found in Parkinson?s disease. Since our veteran populations are at risk for developing Parkinson?s disease as they age, our work will reveal fundamental information on the cause of Parkinson?s disease and provide new insight into ways to prevent and treat Parkinson?s disease. As veterans age, they are also at increased risk of developing viral infections in the brain. Thus, our work will define new mechanisms involved in preventing viral infection in the brain and provide new approaches to prevent or treat veterans with viral infections of the brain. Taken together, our transformational work will have wide-ranging health benefits for our veteran patients across the United States of America.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology E (NURE)
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VA Eastern Colorado Health Care System
United States
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Kashef Hamadani, Bahar H; Franco-Paredes, Carlos; McCollister, Bruce et al. (2018) Cryptococcosis and cryptococcal meningitis: New predictors and clinical outcomes at a United States academic medical centre. Mycoses 61:314-320