Graduation Year

2021

Document Type

Thesis

Degree

M.S.

Degree Name

Master of Science (M.S.)

Degree Granting Department

Medical Sciences

Major Professor

Umesh Jinwal, Ph.D.

Committee Member

Feng Cheng, Ph.D.

Committee Member

Vijaykumar Sutariya, Ph.D.

Keywords

Chaperone proteins, Drug discovery, Neurodegenerative diseases, Hsp90/Cdc37 Complex

Abstract

Neurodegenerative disease refers to the death of specific populations of neurons that canresult in dementia, loss of voluntary muscle motility, and other abnormalities. Two major neurodegenerative diseases are Alzheimer’s disease (AD) and Parkinson’s disease (PD), which are linked to abnormalities in Tau and a-synuclein proteins, respectively. Currently, there is no cure for these diseases. Our group and others have shown that chaperone proteins play a critical role in the processing of Tau and a-synuclein. The inhibition of the Hsp90/Cdc37 chaperone complex is shown to affect the levels of these two proteins. Hence, we hypothesized that a drug molecule, conglobatin (Cb), that has been shown to disrupt this interface will lead to clearance of Tau and a-synuclein. The objective of this study was to test the effect of Cb on the levels of pathogenic neurodegenerative proteins using an in vitro model. M17 neuronal cells stably overexpressing wildtype a-synuclein were treated with increasing doses of Cb. These cells also express detectable levels of endogenous Tau protein. After 24 hours of drug treatment with Cb, the cells were lysed and processed for the western blot analysis using Tau and a-synuclein antibodies. Western blots were quantified using Scion Image software and statistical analysis was performed using GraphPad Prism 9. Data analysis showed that Cb drug cleared Tau and asynuclein effectively. These results validate our hypothesis. Further mechanistic and animal studies are needed to establish this drug as a viable candidate for the treatment of AD, PD, and potentially for other related neurodegenerative disorder

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