Isotropic Reinforcement to Minimize Nigrostriatal Degeneration

Sri International, Menlo Park CA

Investigators

Abstract

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is one of the most common neurodegenerative diseases, affecting 1,500,000 Americans, with 50,000 new cases each year. Currently, therapies are available to alleviate symptoms, but no disease-modifying therapeutic intervention exists. Over thirty years of research indicate that oxidative stress contributes to pathogenesis in PD and the development of alpha-synuclein (a-syn) pathology. However, studies utilizing anti-oxidants show little efficacy. We propose a novel approach to alleviate oxidative injury by utilizing isotopic reinforcement. Toxic reactive oxygen species (ROS) and downstream reactive carbonyl products (RCP) such as 4-hydroxynonenal (4-HNE), are generated in mitochondria. The process of the toxic 4-HNE formation begins with the oxidation of polyunsaturated fatty acids (PUFA). However, substitution of deuterium for hydrogen stabilizes the site of oxidation in PUFA and slows this reaction by up to 80-fold. This kinetic isotope effect reduces the production of 4-HNE and other toxic RCP. Our preliminary data show that MPTP-induced nigrostriatal damage is at least in part reduced by treatment with D-PUFA in mice. We hypothesize that isotopic reinforcement of PUFA will prevent and/or slow progression of degeneration in models of PD and alpha-synucleinopathy. Importantly, if our hypotheses are correct, the window to an entirely new spectrum of therapeutic targets is opened for neurodegenerative and other disorders characterized by oxidative injury.