Parkinson's disease (PD) is a progressive neurodegenerative disorder (ND) that afflicts more than 6 million people worldwide. This number will continue to rise in the coming years as the average age of our society increases. While several risk genes are known to predispose to PD, we still incompletely understand this complex disease and, as a consequence, there are no therapies that slow the progression of this debilitating and ultimately fatal disease. To address this issue, many research groups have searched for new therapeutic targets using simple organisms to model PD pathogenesis. Our lab has previously used the yeast Saccharomyces cerevisiae to pinpoint the cellular functions that mediate the toxicity of the misfolded proteins that cause neurodegenerative disorders, including PD (?-syn), Alzheimer's (A?), Huntington's (polyQ), and ALS (TDP-43). Genetic screens against this yeast ?-syn model have identified suppressors of toxicity that are also protective in neurons. A previous screen of genetically encoded cyclic peptides revealed the presence of a druggable target that protects both yeast and C. elegans neurons from ?-syn toxicity, but the mechanism of action of these compounds remains unknown.
Aim 1 of the current proposal seeks to identify the mechanistic target(s) of these bioactive cyclic peptides using modern chemical biology approaches, including photocrosslinking and cellular thermal shift assays.
In Aim 2, I propose to leverage the genetic tractability of yeast to determine which cellular pathways are necessary and/or sufficient for the protective effect of the cyclic peptides. Finally, in Aim 3 I will leverage recent advances in the technology for screening large libraries o genetically encoded cyclic peptides to develop more efficacious analogs as candidate therapeutics for the treatment of PD and other synucleinopathies. Overall, these studies aim to unveil a new candidate therapeutic target for PD, establish its cellular context, and develop next-generation cyclic peptides that may form the basis of a new class of disease-modifying drugs for PD.

Public Health Relevance

Neurodegenerative disorders, including Parkinson's disease (PD), take an enormous toll on the health of our aging society. Despite remarkable advances in our understanding of the pathology and genetics of PD, today's therapies can only treat a patient's symptoms and do nothing to alter the progression of their disease. The proposed research aims to define the mechanism of action of bioactive cyclic peptides that our group previously discovered to reverse the toxicity caused by the PD-associated protein alpha-synuclein, which may lead to the identification of new therapeutic targets for the treatment of PD and other diseases caused by alpha-synuclein.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS096914-01
Application #
9124060
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sutherland, Margaret L
Project Start
2016-05-01
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code