title: Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement.
abstract: The heme oxygenases (HOs), responsible for the degradation of heme to biliverdin/bilirubin, free iron and CO, have been heavily implicated in mammalian CNS aging and disease. In normal brain, the expression of HO-2 is constitutive, abundant and fairly ubiquitous, whereas HO-1 mRNA and protein are confined to small populations of scattered neurons and neuroglia. In contradistinction to HO-2, the ho-1 gene (Hmox1) is exquisitely sensitive to induction by a wide range of pro-oxidant and other stressors. In Alzheimer disease and mild cognitive impairment, immunoreactive HO-1 protein is over-expressed in neurons and astrocytes of the cerebral cortex and hippocampus relative to age-matched, cognitively intact controls and co-localizes to senile plaques, neurofibrillary tangles, and corpora amylacea. In Parkinson disease, HO-1 is markedly over-expressed in astrocytes of the substantia nigra and decorates Lewy bodies in affected dopaminergic neurons. HMOX1 is also up-regulated in glial cells surrounding human cerebral infarcts, hemorrhages and contusions, within multiple sclerosis plaques, and in other degenerative and inflammatory human CNS disorders. Heme-derived free ferrous iron, CO, and biliverdin/bilirubin are biologically active substances that have been shown to either ameliorate or exacerbate neural injury contingent upon specific disease models employed, the intensity and duration of HO-1 expression and the nature of the prevailing redox microenvironment. In 'stressed' astroglia, HO-1 hyperactivity promotes mitochondrial sequestration of non-transferrin iron and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure amply documented in Alzheimer disease, Parkinson disease and other aging-related neurodegenerative disorders. Glial HO-1 expression may also impact cell survival and neuroplasticity in these conditions by modulating brain sterol metabolism and proteosomal degradation of neurotoxic protein aggregates.
authors.affiliation: Centre for Neurotranslational Research, Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada. hyman.schipper@mcgill.ca
authors.forename: Hyman M
authors.initials: HM
authors.lastname: Schipper
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Hillel
authors.initials: H
authors.lastname: Zukor
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Hascalovici
authors.forename: David
authors.initials: D
authors.lastname: Zeligman
mesh_terms: D000818:Animals; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051547:Heme Oxygenase-1