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

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)312-322
Number of pages11
JournalNeurobiology of Disease
Volume26
Issue number2
DOIs
StatePublished - May 2007

Keywords

  • Alpha-synuclein
  • DSP-4
  • Dopamine
  • Locus coeruleus
  • MPTP
  • Norepinephrine
  • Parkin
  • Parkinson's disease
  • Substantia nigra

ASJC Scopus subject areas

  • Neurology

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    Thomas, B., von Coelln, R., Mandir, A. S., Trinkaus, D. B., Farah, M. H., Leong Lim, K., Calingasan, N. Y., Flint Beal, M., Dawson, V. L., & Dawson, T. M. (2007). MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity. Neurobiology of Disease, 26(2), 312-322. https://doi.org/10.1016/j.nbd.2006.12.021