Title

The Role of Advanced Glycation End Products (AGEs) through the TRPA-1/NRF-2 Activation Pathway in the Neurodegenerative Diseases

Graduation Date

5-2017

Document Type

Master's Thesis

Degree Name

Master of Science

Department or Program

Biological Sciences

Department or Program Chair

Maggie Louie, Ph.D.

First Reader

Pankaj Kapahi, Ph.D.

Second Reader

Kiowa Bower, Ph.D.

Abstract

The posttranslational modification of macromolecules caused by highly reactive and toxic α-dicarbonyls, such as methylglyoxal (MGO) derived from glycolysis, is associated with various age-related diseases including diabetic complications and neurodegenerative diseases. Aging and long-term hyperglycemia causes enhanced production of this highly reactive α-dicarbonyl, which reacts with macromolecules causing irreversible damage of DNA and protein promoting the formation of advanced glycation end products (AGEs). The formation and accumulation of AGEs in different cell types affect intracellular and extracellular structure and function. AGEs can also cause macrovascular and microvascular complications through the formation of cross-links between key molecules, permanently altering cellular structure (Brownlee, 2001). Several proteins implicated in neurodegenerative diseases, such as α-synuclein, are glycated and the degree of glycation is associated with various pathologies (Wang et al., 2014). Under physiological circumstances, α-dicarbonyls are detoxified by a set of glyoxalase enzymes, glyoxalase I (GLO1) and glyoxalase II (GLO II), that are responsible for catalyzing MGO into D-lactate preventing the formation of AGEs. Therefore, preventing the formation of excessive AGE buildup is essential for limiting the progression of various debilitating age-related disorders. The focus of this project is to investigate the biochemical mechanisms of MGO/AGE accumulation to allow for discovery of pharmacological targets relevant to secondary diabetic complications and neurodegenerative disorders where these toxic metabolites play an important role. We purpose that amelioration of MGO/AGE-related stress have an important role to play in the treatment option for diabetic pathologies and neurodegenerative disorders, such as Parkinson’s disease. To study this further, we investigated the cytotoxic effects of MGO/AGEs by using dopaminergic mammalian cell models (N27 and PC12 cell lines) that are established for its relevance to Parkinson’s disease (PD) in order to understand the biochemical role behind these reactive metabolites to identify novel therapeutic compounds that can ameliorate these harmful effects (Alberio, Lopiano, & Fasano, 2012). Essentially, examine the relationship between secondary complications of diabetic neuropathy and Parkinson’s disease (PD), with special relevance to neurotoxic effects of methylglyoxal and advanced glycation end products.

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