Parkinson disease (PD) is the most common movement disorder affecting over one million people in North America alone and results in an insidious reduction in the quality of life and ability to function. A hallmark of PD is the brain accumulation of neuronal cytoplasmic inclusions comprised of the protein a-synuclein, but the presence of ?-synuclein brain aggregates is observed in a spectrum of neurodegenerative diseases, including dementia with Lewy body. Several findings suggest that ?-synuclein amyloid pathology may spread during disease progression by a self-templating alteration in protein conformation mechanism, however other alternative and/or synergistic biological mechanisms, as supported by our data, could also lead to progression of ?-synuclein pathology. From a therapeutic aspect it is critical to determine the relative importance, mechanisms and physiological consequences of the spread of ?-synuclein aggregation in disease. It this proposal, two major specific aims are proposed to inform on ?-synuclein induced and spread of disease: 1) Using both wild-type and disease causing mutant forms of ?-synuclein with unique aggregation properties, we will directly investigated that a-synuclein aggregation can spread within the central nervous system and from the periphery with specific conformational characteristics. 2) We will assess the importance of alternative biological mechanisms including perturbation of the protein network homeostasis, neuronal intermediate filament integrity, neurotoxicity and age-related changes in the induction and propagation of ?-synuclein pathology by exogenous a-synuclein challenges. These studies will provide critical insights on the mechanisms and the involvement of ?-synuclein aggregation in PD disease progression with the objective of guiding the development of novel therapeutics.

Public Health Relevance

Parkinson disease is an insidious neurodegenerative disease, affecting ~1% of the population over 65 years of age. Progressive aggregation and inclusion formation of the protein ?-synuclein is a hallmark of this disorder and the planned research project focuses on understanding the underlying biological and molecular mechanisms involved in the development of disease with the objective of guiding novel therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS089622-05
Application #
9545083
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2014-09-15
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Florida
Department
Neurosciences
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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