Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial parkinsonism-linked gene DJ-1

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  • Goldberg, Matthew S.
    • Other Affiliation: Center for Neurologic Diseases, Brigham and Women’s Hospital, Program in Neuroscience, Harvard Medical School
  • Pisani, Antonio
    • Other Affiliation: Department of Neuroscience, University of Rome Tor Vergata and Fondazione Santa Lucia IRCCS, Rome, Italy
  • Haburcak, Marian
    • Other Affiliation: Department of Pharmacology , and Experimental Therapeutics, Tufts University School of Medicine
  • Vortherms, Timothy A.
    • Other Affiliation: Departments of Biochemistry, Psychiatry , and Neurosciences, Case Western Reserve University Medical School
  • Kitada, Tohru
    • Other Affiliation: Center for Neurologic Diseases, Brigham and Women’s Hospital, Program in Neuroscience, Harvard Medical School
  • Costa, Cinzia
    • Other Affiliation: Department of Neuroscience, University of Rome Tor Vergata and Fondazione Santa Lucia IRCCS, Rome, Italy
  • Tong, Youren
    • Other Affiliation: Center for Neurologic Diseases, Brigham and Women’s Hospital, Program in Neuroscience, Harvard Medical School
  • Martella, Giuseppina
    • Other Affiliation: Department of Neuroscience, University of Rome Tor Vergata and Fondazione Santa Lucia IRCCS, Rome, Italy
  • Tscherter, Anne
    • Other Affiliation: Department of Neuroscience, University of Rome Tor Vergata and Fondazione Santa Lucia IRCCS, Rome, Italy
  • Martins, Andrea
    • Other Affiliation: Center for Neurologic Diseases, Brigham and Women’s Hospital, Program in Neuroscience, Harvard Medical School
  • Bernardi, Giorgio
    • Other Affiliation: Department of Neuroscience, University of Rome Tor Vergata and Fondazione Santa Lucia IRCCS, Rome, Italy
  • Roth, Bryan L.
  • Pothos, Emmanuel N.
    • Other Affiliation: Department of Pharmacology, and Experimental Therapeutics, Tufts University School of Medicine
  • Calabresi, Paolo
    • Other Affiliation: Department of Neuroscience, University of Rome Tor Vergata and Fondazione Santa Lucia IRCCS, Rome, Italy
  • Shen, Jie
    • Other Affiliation: Center for Neurologic Diseases, Brigham and Women’s Hospital, Program in Neuroscience, Harvard Medical School
Abstract
  • The manifestations of Parkinson’s disease are caused by reduced dopaminergic innervation of the striatum. Loss-of-function mutations in the DJ-1 gene cause early-onset familial parkinsonism. To investigate a possible role for DJ-1 in the dopaminergic system, we generated a mouse model bearing a germline disruption of DJ-1. Although DJ-1−/− mice had normal numbers of dopaminergic neurons in the substantia nigra, evoked dopamine overflow in the striatum was markedly reduced, primarily as a result of increased reuptake. Nigral neurons lacking DJ-1 were less sensitive to the inhibitory effects of D2 autoreceptor stimulation. Corticostriatal long-term potentiation was normal in medium spiny neurons of DJ-1−/− mice, but long-term depression (LTD) was absent. The LTD deficit was reversed by treatment with D2 but not D1 receptor agonists. Furthermore, DJ-1−/− mice displayed hypoactivity in the open field. Collectively, our findings suggest an essential role for DJ-1 in dopaminergic physiology and D2 receptor-mediated functions.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Neuron
Journal volume
  • 45
Journal issue
  • 4
Page start
  • 489
Page end
  • 496
Language
  • English
Version
  • Postprint
ISSN
  • 0896-6273

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