MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity

Bobby Thomas; Rainer von Coelln; Allen S. Mandir; Daniel B. Trinkaus; Mohamed H. Farah; Kah Leong Lim; Noel Y. Calingasan; M. Flint Beal; Valina L. Dawson; Ted M. Dawson

Neurobiology of Disease (May 2007)

MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity

Bobby Thomas,
Rainer von Coelln,
Allen S. Mandir,
Daniel B. Trinkaus,
Mohamed H. Farah,
Kah Leong Lim,
Noel Y. Calingasan,
M. Flint Beal,
Valina L. Dawson,
Ted M. Dawson

Affiliations

Bobby Thomas: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, A-501, New York, NY 10021, USA
Rainer von Coelln: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Allen S. Mandir: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Daniel B. Trinkaus: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Mohamed H. Farah: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Kah Leong Lim: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Noel Y. Calingasan: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, A-501, New York, NY 10021, USA
M. Flint Beal: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, A-501, New York, NY 10021, USA
Valina L. Dawson: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Ted M. Dawson: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author. Institute for Cell Engineering, Johns Hopkins University, 733 N. Broadway, Suite 731, Baltimore, MD 21205, USA. Fax: +1 410 614 9568.

Journal volume & issue: Vol. 26, no. 2
pp. 312 – 322

Abstract

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Mutations in the parkin gene cause autosomal recessive familial Parkinson's disease (PD). Parkin-deficient mouse models fail to recapitulate nigrostriatal dopaminergic neurodegeneration as seen in PD, but produce deficits in dopaminergic neurotransmission and noradrenergic-dependent behavior. Since sporadic PD is thought to be caused by a combination of genetic susceptibilities and environmental factors, we hypothesized that neurotoxic insults from catecholaminergic toxins would render parkin knockout mice more vulnerable to neurodegeneration. Accordingly, we investigated the susceptibility of catecholaminergic neurons in parkin knockout mice to the potent dopaminergic and noradrenergic neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) respectively. We report that nigrostriatal dopaminergic neurons in parkin knockout mice do not show increased susceptibility to the parkinsonian neurotoxin, MPTP, in acute, subacute and chronic dose regimens of the neurotoxin. Additionally, parkin knockout mice do not show increased vulnerability to the noradrenergic neurotoxin, DSP-4, regarding levels of norepinephrine in cortex, brain stem and spinal cord. These findings suggest that absence of parkin in mice does not increase susceptibility to the loss of catecholaminergic neurons upon exposure to both dopaminergic and noradrenergic neurotoxins.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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