Neural Heme Oxygenase-1 Expression in Idiopathic Parkinson's Disease

doi:10.1006/exnr.1997.6752

Experimental Neurology

Volume 150, Issue 1, March 1998, Pages 60-68

https://doi.org/10.1006/exnr.1997.6752 Get rights and content

Abstract

Heme oxygenase-1 is a cellular stress protein expressed in brain and other tissues in response to oxidative challenge and other noxious stimuli. In the present study, immunohistochemistry was used to assess HO-1 expression in various postmortem human brain specimens derived from PD and control subjects. In the substantia nigra of both PD and control specimens, moderate HO-1 immunoreactivity was consistently observed in neuromelanin-containing (dopaminergic) neurons. Lewy bodies in PD nigra neurons exhibited intense HO-1 immunostaining in their peripheries. In both PD and control specimens, neuronal HO-1 staining was faint or nondetectable in the other brain regions surveyed. The fraction of GFAP-positive astroglia expressing HO-1 in PD substantia nigra (77.1 ± 12.3) was significantly greater than that observed in the substantia nigra of control subjects (18.7 ± 7.1;P = 0.0015). In the other regions examined, percentages of GFAP-positive astroglia coexpressing HO-1 were relatively low and did not differ significantly (P > 0.05) between control and PD specimens. Upregulation of HO-1 in the substantia nigra of PD subjects supports the view that the affected tissue is experiencing chronic oxidative stress. In addition, excessive cellular levels of heme-derived free iron and carbon monoxide resulting from HO-1 overactivity may contribute to the pathogenesis of PD.

References (51)

J.L. Cadet et al.
Vitamin E attenuates the toxic effects of intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats: Behavioral and biochemical evidence
Brain Res.
(1989)
F. Hefti et al.
Partial lesions of the dopaminergic nigrostiatal system in rat brain: biochemical characterization
Brain Res.
(1980)
M. Mogi et al.
bcl-2 Protein is increased in the brain from parkinsonian patients
Neurosci. Lett.
(1996)
M. Parenti et al.
Role of dopamine in manganese neurotoxicity
Brain Res.
(1988)
H.R.B. Pelham
Activation of heat-shock genes in eukaryotes
Trends Genet.
(1985)
N. Perez et al.
Increased synthesis and accumulation of heat shock 70 proteins in Alzheimer's disease
Mol. Brain Res.
(1991)
T.L. Perry et al.
Parkinson's disease: A disorder due to nigral glutathione deficiency
Neurosci. Lett.
(1982)
T. Peterson et al.
The role of heme oxygenase and aryl hydrocarbon hydroxylase in the protection by cysteamine from acetaminophen hepatotoxicity
Toxicol. Appl. Pharmacol.
(1989)
H.M. Schipper et al.
Glial peroxidase activity in the hypothalamic arcuate nucleus: Effects of estradiol valerate-induced persistent estrus
Brain Res.
(1990)
R. Tenhunen et al.
Microsomal heme oxygenase: Characterization of the enzyme
J. Biol. Chem.
(1969)

G.P. Wang et al.

Brain ubiquitin is markedly elevated in Alzheimer disease

Brain Res.

(1991)

L.M. Ambani et al.

Brain peroxidase and catalase in Parkinson's disease

Arch. Neurol.

(1975)

P. Anglade et al.

Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease

Histol. Histopathol.

(1997)

L.A. Applegate et al.

Induction of heme oxygenase: A general response to oxidant stress in cultured mammalian cells

Cancer Res.

(1991)

A. Barbeau

Etiology of Parkinson's disease: A research strategy

Can. J. Neurol. Sci.

(1984)

M.F. Beal

Mitochondrial Dysfunction and Oxidative Damage in Neurodegenerative Diseases

(1995)

D.E. Bredesen

Neural apoptosis

Ann. Neurol.

(1995)

D.B. Calne

Initiating treatment for idiopathic parkinsonism

Neurology

(1994)

Cohen, G. 1987, Oxygen radicals and Parkinson's disease, 130, 135, Upjohn Symposium on Oxygen Radicals, Augusta,...

G. Cohen et al.

Free radicals, oxidative stress, and neurodegeneration

Neurodegenerative Diseases

(1994)

D.T. Dexter et al.

Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease

J. Neurochem.

(1989)

D.T. Dexter et al.

Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease

J. Neurochem.

(1989)

B.E. Dwyer et al.

Heme oxygenase is a heat shock protein and PEST protein in rat astroglial cells

Glia

(1992)

J.F. Ewing et al.

Normal and heat-induced patterns of expression of heme oxygenase-1 (HSP32) in rat brain: Hyperthermia causes rapid induction of mRNA and protein

J. Neurochem.

(1992)

J.F. Ewing et al.

Rapid induction of heme oxygenase 1 mRNA and protein by hyperthermia in rat brain: Heme oxygenase 2 is not a heat shock protein

Proc. Natl. Acad. Sci. USA

(1991)

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^☆: D. B. Calne

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Regular ArticleNeural Heme Oxygenase-1 Expression in Idiopathic Parkinson's Disease☆

Abstract

Brain Res.

Brain Res.

Neurosci. Lett.

Brain Res.

Trends Genet.

Mol. Brain Res.

Neurosci. Lett.

Toxicol. Appl. Pharmacol.

Brain Res.

J. Biol. Chem.

Brain Res.

Brain peroxidase and catalase in Parkinson's disease

Arch. Neurol.

Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease

Histol. Histopathol.

Induction of heme oxygenase: A general response to oxidant stress in cultured mammalian cells

Cancer Res.

Etiology of Parkinson's disease: A research strategy

Can. J. Neurol. Sci.

Mitochondrial Dysfunction and Oxidative Damage in Neurodegenerative Diseases

Neural apoptosis

Ann. Neurol.

Initiating treatment for idiopathic parkinsonism

Neurology

Free radicals, oxidative stress, and neurodegeneration

Neurodegenerative Diseases

Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease

J. Neurochem.

Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease

J. Neurochem.

Heme oxygenase is a heat shock protein and PEST protein in rat astroglial cells

Glia

Normal and heat-induced patterns of expression of heme oxygenase-1 (HSP32) in rat brain: Hyperthermia causes rapid induction of mRNA and protein

J. Neurochem.

Rapid induction of heme oxygenase 1 mRNA and protein by hyperthermia in rat brain: Heme oxygenase 2 is not a heat shock protein

Proc. Natl. Acad. Sci. USA

Regular Article
Neural Heme Oxygenase-1 Expression in Idiopathic Parkinson's Disease☆