In aging vertebrates, subpopulations of limbic and periventricular astrocytes accumulate peroxidase-positive cytoplasmic inclusions distinct from lipofuscin. In rodent brain, chronic estrogenization accelerates the appearance of this senescent glial phenotype. Identical inclusions are rapidly induced in primary neuroglial cultures by cysteamine exposure. Abnormal mitochondria replete with redox-active iron and other transition metals are the subcellular precursors of the inclusions in situ and in cysteamine-treated cultures. The objective of this thesis was to elucidate mechanisms responsible for the biogenesis of these glial inclusions in the aging nervous system. / We determined that the accumulation of astrocytic inclusions in cysteamine-treated rat glial cultures occurs in the context of an antecedent cellular stress response characterized by (i) the upregulation of heat shock proteins (HSP) 27, 72, 90, ubiquitin and heme oxygenase-1, and (ii) enhanced resistance of cysteamine-stressed astroglia to subsequent oxidative injury. Furthermore, multiple injections of cysteamine or estradiol valerate in adult male rats induced robust overexpression of stress proteins and an accretion of identical peroxidase-positive granules in GFAP-positive astroglia. Both in situ and in cysteamine-treated cultures, HSP27, ubiquitin, glucose-regulated protein 94 and to a lesser extent, HSP72 (but not HSP90 or $ alpha$B-crystallin) exhibited immunolocalization to these astrocytic "stress" inclusions. We observed that exogenous $ rm H sb2O sb2$ induces identical inclusions in cultured astroglia and that cysteamine-derived $ rm H sb2O sb2$ promotes lipid peroxidation in isolated astroglial mitochondria. These data indicate that sustained oxidative stress may represent a "final common pathway" leading to the transformation of normal mitochondria to peroxidase-positive astrocytic inclusions in the aging nervous system. / The metal-dependent peroxidase activity of these glial inclusions has been shown to oxidize dopamine and other catechols to neurotoxic free radicals in vitro, implicating these cells in the pathogenesis of parkinsonism and other free radical-related neurodegenerations. Since peroxidase-positive astroglia have been identified in aging human striatum, the findings presented here suggest that antioxidant therapy coupled with pharmacological inhibition of metal sequestration by "stressed" astroglial mitochondria may prove useful in the management of Parkinson's disease and other age-associated neurodegenerative afflictions.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.39970 |
| Date | January 1995 |
| Creators | Mydlarski, Marc Bernard |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Neurology and Neurosurgery.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001480950, proquestno: NN12444, Theses scanned by UMI/ProQuest. |
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