New strategies to treat neurodegenerative disease through modulation of mitochondria function
Abstract
Neurodegenerative diseases are categorized into familial forms, where the diseases are inherited by a mutation in specific genes, or sporadic forms, which is induced by unknown factors. Although the actual causes of these diseases are unclear, mitochondrial dysfunction is becoming increasingly recognized as an early and common feature. In this study, modulation of Parkinson's disease phenotypes are investigated through approaches in a genetic and environmental manner, focused on modulation of mitochondrial activity. We demonstrate that dosage reduction of Activated Cdc42 Kinase (Ack), a member of the non-receptor tyrosine kinase family, is able to suppress Pink1 B9 phenotypes such as thoracic indentation, abnormal wing posture, sterility, sensitivity to Paraquat, and reduced complex I activity in the electron transport chain. Along with Ack, dosage reduction of Yorkie, a transcriptional co-activator reported to interact with Ack also rescued Pink1B9 phenotypes. In addition, we also discovered that common food preservatives, methyl paraben (MP) and benzoic acid (BA) can modulate mitochondrial complex activities and oxidation consumption rates. Surprisingly these environmental factors were able to influence PD thoracic indentation and expressivity phenotypes induced by Pink1 and Parkin gene mutations. Our findings demonstrate that environmental and genetic factors can robustly interact to modify PD phenotypes and by determining the interaction of these two factors, we propose that environmental modification can either slow down or inhibit the onset of familial and sporadic PD, and potentially, other neurodegenerative diseases exhibiting dysfunctional mitochondria.
Degree
Ph.D.
Advisors
Clemens, Purdue University.
Subject Area
Pharmacology|Biochemistry|Aging|Immunology
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