Neurochemical investigations of dopamine neuronal systems in iron-regulatory protein 2 (IRP-2) knockout mice

Michael Francis Salvatore, Brent Fisher, Stewart P. Surgener, Greg A. Gerhardt, Tracey Rouault

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27 Citations (Scopus)

Abstract

Abnormal iron accumulations are frequently observed in the brains of patients with Parkinson's disease and in normal aging. Iron metabolism is regulated in the CNS by iron regulatory proteins (IRP-1 and IRP-2). Mice engineered to lack IRP-2 develop abnormal motoric behaviors including tremors at rest, abnormal gait, and bradykinesia at middle to late age (18 to 24 months). To further characterize the dopamine (DA) systems of IRP-2 -/- mice, we harvested CNS tissue from age-matched wild type and IRP-2 -/- (16-19 months) and analyzed the protein levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), and DA levels in dorsal striatum, ventral striatum (including the core and shell of nucleus accumbens), and midbrain. We further analyzed the phosphorylation of TH in striatum at serine 40, serine 31, and serine 19. In both dorsal and ventral striatum of IRP-2 knockout mice, there was a 20-25% loss of TH protein and accompanied by a ∼50% increase in serine 40 phosphorylation above wild-type levels. No change in serine 31 phosphorylation was observed. In the ventral striatum, there was also a significant loss (∼40%) of DAT and VMAT2. Levels of DA were decreased (∼20%) in dorsal striatum, but turnover of DA was also elevated (∼30%) in dorsal striatum of IRP-2 -/- mice. We conclude that iron misregulation associated with the loss of IRP-2 protein affects DA regulation in the striatum. However, the modest loss of DA and DA-regulating proteins does not reflect the pathology of PD or animal models of PD. Instead, these observations support that the IRP-2 -/- genotype may enable neurobiological events associated with aging.

Original languageEnglish
Pages (from-to)341-347
Number of pages7
JournalMolecular Brain Research
Volume139
Issue number2
DOIs
StatePublished - 3 Oct 2005

Fingerprint

Iron Regulatory Protein 2
Knockout Mice
Dopamine
Serine
Tyrosine 3-Monooxygenase
Dopamine Plasma Membrane Transport Proteins
Iron
Phosphorylation
Iron Regulatory Protein 1
Proteins
Vesicular Monoamine Transport Proteins
Hypokinesia
Nucleus Accumbens
Tremor
Mesencephalon
Gait
Parkinson Disease
Animal Models
Genotype

Keywords

  • Dopamine
  • IRP-2
  • Iron metabolism
  • Striatum
  • Tyrosine hydroxylase

Cite this

Salvatore, Michael Francis ; Fisher, Brent ; Surgener, Stewart P. ; Gerhardt, Greg A. ; Rouault, Tracey. / Neurochemical investigations of dopamine neuronal systems in iron-regulatory protein 2 (IRP-2) knockout mice. In: Molecular Brain Research. 2005 ; Vol. 139, No. 2. pp. 341-347.
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abstract = "Abnormal iron accumulations are frequently observed in the brains of patients with Parkinson's disease and in normal aging. Iron metabolism is regulated in the CNS by iron regulatory proteins (IRP-1 and IRP-2). Mice engineered to lack IRP-2 develop abnormal motoric behaviors including tremors at rest, abnormal gait, and bradykinesia at middle to late age (18 to 24 months). To further characterize the dopamine (DA) systems of IRP-2 -/- mice, we harvested CNS tissue from age-matched wild type and IRP-2 -/- (16-19 months) and analyzed the protein levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), and DA levels in dorsal striatum, ventral striatum (including the core and shell of nucleus accumbens), and midbrain. We further analyzed the phosphorylation of TH in striatum at serine 40, serine 31, and serine 19. In both dorsal and ventral striatum of IRP-2 knockout mice, there was a 20-25{\%} loss of TH protein and accompanied by a ∼50{\%} increase in serine 40 phosphorylation above wild-type levels. No change in serine 31 phosphorylation was observed. In the ventral striatum, there was also a significant loss (∼40{\%}) of DAT and VMAT2. Levels of DA were decreased (∼20{\%}) in dorsal striatum, but turnover of DA was also elevated (∼30{\%}) in dorsal striatum of IRP-2 -/- mice. We conclude that iron misregulation associated with the loss of IRP-2 protein affects DA regulation in the striatum. However, the modest loss of DA and DA-regulating proteins does not reflect the pathology of PD or animal models of PD. Instead, these observations support that the IRP-2 -/- genotype may enable neurobiological events associated with aging.",
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Neurochemical investigations of dopamine neuronal systems in iron-regulatory protein 2 (IRP-2) knockout mice. / Salvatore, Michael Francis; Fisher, Brent; Surgener, Stewart P.; Gerhardt, Greg A.; Rouault, Tracey.

In: Molecular Brain Research, Vol. 139, No. 2, 03.10.2005, p. 341-347.

Research output: Contribution to journalArticleResearchpeer-review

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