Astrocytes and glutamatergic dysfunction in manganese neurotoxicity

• Grant number: 13/02938-6
• Support Opportunities: Research Grants - Visiting Researcher Grant - International
• Duration: April 04, 2013 - April 03, 2014
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fernando Cendes
• Grantee: Fernando Cendes
• Visiting researcher: Alan Stewart Hazell
• Visiting researcher institution: Université de Montréal, Canada
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The manganese neurotoxicity (MN) model, with its well-established metabolic dysfunction and selective vulnerability, is a valuable system with which to elucidate the relationship between chronic impairment of energy metabolism and selective neuronal cell death. Thus far, our understanding of the pathophysiology underlying MN is limited. In the proposed studies, we are taking an important step towards better understanding the nature of the structural damage that results in the basal ganglia in this disorder by investigating the phenomenon of excitotoxicity. We expect our findings will yield new insight into the pathophysiologic mechanisms that lead to this brain disorder as well as other disease processes in which cerebral accumulation of manganese occurs, e.g. portal-systemic encephalopathy. In addition, since recent evidence suggests that MN may be a contributing factor in idiopathic Parkinson's disease, our studies may provide information on how these cases may arise and the underlying mechanism. Finally, recent studies indicate that neurodegenerative disease states such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and the devastating Guamanian disorder ALS-parkinsonism-dementia-complex also exhibit alterations in glutamate transporters, and involve alterations in oxidative metabolism as in MN. Thus, we believe that identification of the processes involved in MN-induced excitotoxic cell death could provide important details in the quest to explain not only the causes of selective vulnerability in this disorder but also those inherent in other neurodegenerative maladies, along with potential therapeutic targeting strategies. (AU)