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PMID: 15721235 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Neuron ·Vol. 45 ·No. 4 ·2005-02-17 ·Pages 489-96

Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P, Shen J

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.

MeSH Terms

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology Age Factors Animals Behavior, Animal Blotting, Southern/methods Blotting, Western/methods Cell Count Cerebral Cortex/cytology,physiology Disease Models, Animal Dopamine/deficiency Dopamine Agonists/pharmacology Dopamine Plasma Membrane Transport Proteins Electric Stimulation/methods Electrochemistry/methods Excitatory Postsynaptic Potentials/drug effects,physiology Germ-Line Mutation Humans Hypokinesia/physiopathology Immunohistochemistry/methods In Vitro Techniques Intracellular Signaling Peptides and Proteins Membrane Glycoproteins/metabolism Membrane Transport Proteins/metabolism Mice Mice, Inbred C57BL Mice, Transgenic Nerve Tissue Proteins/metabolism Neurons/physiology Oncogene Proteins/physiology Parkinsonian Disorders/genetics,metabolism Protein Deglycase DJ-1 Quinpirole/pharmacology RNA, Messenger/biosynthesis Radioligand Assay/methods Receptors, Dopamine D2/metabolism Reverse Transcriptase Polymerase Chain Reaction/methods Substantia Nigra/cytology,drug effects,metabolism Tyrosine 3-Monooxygenase/metabolism

Chemicals

Dopamine Agonists Dopamine Plasma Membrane Transport Proteins Intracellular Signaling Peptides and Proteins Membrane Glycoproteins Membrane Transport Proteins Nerve Tissue Proteins Oncogene Proteins RNA, Messenger Receptors, Dopamine D2 Quinpirole 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine Tyrosine 3-Monooxygenase PARK7 protein, human Protein Deglycase DJ-1 Dopamine

Authors & Affiliations

15 authors, click to expand affiliations / ORCID

Goldberg Matthew S

Center for Neurologic Diseases, Brigham & Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.

Pisani Antonio

Haburcak Marian

Vortherms Timothy A

Kitada Tohru

Costa Cinzia

Tong Youren

Martella Giuseppina

Tscherter Anne

Martins Andrea

Bernardi Giorgio

Roth Bryan L

Pothos Emmanuel N

Calabresi Paolo

Shen Jie

Article Info

Journal

Neuron

Abbr.

Neuron

ISSN

0896-6273

DOI

10.1016/j.neuron.2005.01.041

Published

2005-02-17

Pages

489-96

Language

English

Region

United States

NLM ID

8809320

Subset

Corrections

CommentIn

PMID: 15721232

External Links

PubMed source DOI: 10.1016/j.neuron.2005.01.041 View journal details

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

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