Striatal vulnerability to mitochondrial inhibition

The relative vulnerability of the striatum and of subpopulations of cells within the striatum to many acute and chronic neurodegenerative conditions has been well established. Neurodegenerative events such as ischemia, Huntington\u27s disease and ingestion of mitochondrial toxins which target the striatum share the common feature of energetic failure as a critical early part of the cell death process. The purpose of this thesis was to evaluate how striatal cells respond to energetic failure, to determine if these neurons are more inherently vulnerable to mitochondrial inhibition than other kinds of neurons and to evaluate the role of the unique circuitry of the striatum in mediating selective striatal cell death. The first part of this work evaluated the biochemical, molecular and morphological effects of energetic failure induced by the mitochondrial toxin methylmalonate in vitro. The major findings of this portion of the work were that methylmalonate: (1) inhibits mitochondrial respiration and causes dose dependent cell death which is not appreciably different in primary cultures of striatal versus cortical cells; (2) causes an early disruption of ion homeostasis and membrane depolarization and (3) induced apoptotic cell death predominantly which can be attenuated with the addition of antioxidants. These findings suggested that extrinsic or developmental factors may be of greater importance in mediating striatal vulnerability to energetic failure. To address this question, the next portion of this thesis was devoted to determining whether or not dopamine, which is abundant in the striatum, and released in large quantities during many insults to the CNS, is neurotoxic and if it potentiates the cell death caused by energetic failure. The major findings of these studies were that: (1) dopamine induces massive apoptotic striatal cells at concentrations similar to those observed in vivo during acute CNS trauma; (2) dopamine mediated cell death is due primarily to production of free radicals and, to a lesser extent, to toxic activation of D1 receptors; (3) dopamine dramatically increases the amount of cell death caused by subtoxic doses of methylmalonate and (4) this increased toxicity is likely caused by convergent production of free radicals as it can be halted in the presence of antioxidants. This work characterizes a novel and biologically significant compound and system for studying acute and chronic neurodegenerative events and appreciably extends our understanding of how intrinsic factors within the striatum as well as the unique circuitry of the basal ganglia contribute to striatal vulnerability to neurodegeneration