Abstract
Heme oxygenase-1 (HO-1) is a 32 kDa protein which catalyzes the breakdown of heme to free iron, carbon monoxide and biliverdin. The Hmox1 promoter contains numerous consensus sequences that render the gene exquisitely sensitive to induction by diverse pro-oxidant and inflammatory stimuli. In “stressed” astroglia, HO-1 hyperactivity promotes mitochondrial iron sequestration and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure documented in Alzheimer disease, Parkinson disease and certain neurodevelopmental conditions. Glial HO-1 expression may also impact neuroplasticity and cell survival by modulating brain sterol metabolism and the proteasomal degradation of neurotoxic proteins. The glial HO-1 response may represent a pivotal transducer of noxious environmental and endogenous stressors into patterns of neural damage and repair characteristic of many human degenerative and developmental CNS disorders.
Highlights
Heme oxygenase-1 (HO-1) is a 32 kDa protein which catalyzes the breakdown of heme to free iron, carbon monoxide and biliverdin
We review evidence that (1) iron deposition, oxidative stress (OS), mitochondrial injury and macroautophagy constitute a single neuropathological “lesion” which may foster progression of various degenerative and developmental brain disorders and (2) these ubiquitous neuropathological changes result from the over-expression of astroglial heme oxygenase-1 (HO-1) in the affected neural tissues
Disease and cell culture experiments, we posited that augmented iron deposition, oxidative stress, mitochondrial insufficiency and macroautophagy which have been amply documented in numerous chronic brain disorders may be viewed as a single neurohistopathological “lesion”, with the advent of one component facilitating the appearance of the others [1]
Summary
Human neurodegenerative and neurodevelopmental disorders vary with respect to risk factors, sex predilections, ages of onset, regions of the neuraxis involved, behavioral and neurological symptoms, hallmark cellular inclusions (if any), neurochemical disturbances, structural and functional neuroimaging, and electrophysiology. A second approach, and the focus of our laboratory, is to delineate “core” neuropathological mechanisms operating in many, if not all, chronic CNS disorders and develop therapeutic strategies targeting these shared manifestations. While this approach may not directly address disease “etiology” (which may differ substantially among the diverse entities), it may disrupt salient common pathways that drive disease “pathogenesis” and thereby achieve meaningful clinical outcomes. We conclude by suggesting that glial HMOX1 induction, while conferring certain neuroprotective benefits, may be a pivotal transducer of noxious ambient stimuli (risk factors) into patterns of aberrant brain structure and function in various human degenerative and developmental CNS disorders
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