Journal
NEUROBIOLOGY OF AGING
Volume 58, Issue -, Pages 163-179Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2017.06.017
Keywords
alpha-Synuclein; Astrocyte; Dopamine; Heme oxygenase-1; Mitochondrial dysfunction; Oxidative stress; Parkinson disease
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Funding
- Canadian Institutes of Health Research Grant [MOP-68887]
- Mary Katz Claman Foundation
- ApoPharma Inc
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Epigenetic influences mediating brain iron deposition, oxidative mitochondrial injury, and macro-autophagy in Parkinson disease and related conditions remain enigmatic. Here, we show that selective overexpression of the stress protein, heme oxygenase-1 (HO-1) in astrocytes of GFAP.HMOX1 transgenic mice between 8.5 and 19 months of age results in nigrostriatal hypodopaminergia associated with locomotor incoordination and stereotypy; downregulation of tyrosine hydroxylase, DAT, LMX1B, Nurr1, Pitx3 and DJ-1 mRNA and/or protein; overproduction of a-synuclein and ubiquitin; oxidative stress; basal ganglia siderosis; mitochondrial damage/mitophagy; and augmented GABAergic systems (increased GABA, GAD67 and reelin). The neurophenotype of these GFAP.HMOX1(8.5-19m) mice is highly consistent with parkinsonism and differs dramatically from the schizophrenia-like features previously documented in younger GFAP. HMOX1(0-12m) mice. Common stressors may elicit either early-onset developmental (schizophrenia) or later-life degenerative (PD) brain disorders depending on whether the glial HO-1 response is engaged prior to or following the maturation of dopaminergic circuitry. Curtailment of glial HO-1 transduction at strategic points of the life course may confer neuroprotection in human degenerative and developmental central nervous system disorders. (C) 2017 Elsevier Inc. All rights reserved.
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