Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1.
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.
Goldberg
Matthew S
MS
Center for Neurologic Diseases, Brigham & Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
Pisani
Antonio
A
Haburcak
Marian
M
Vortherms
Timothy A
TA
Kitada
Tohru
T
Costa
Cinzia
C
Tong
Youren
Y
Martella
Giuseppina
G
Tscherter
Anne
A
Martins
Andrea
A
Bernardi
Giorgio
G
Roth
Bryan L
BL
Pothos
Emmanuel N
EN
Calabresi
Paolo
P
Shen
Jie
J
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal; D015139:Blotting, Southern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency*; D018491:Dopamine Agonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D004558:Electric Stimulation / Q000379:methods; D004563:Electrochemistry / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018095:Germ-Line Mutation; D006801:Humans; D018476:Hypokinesia / Q000503:physiopathology*; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D015513:Oncogene Proteins / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1; D019257:Quinpirole / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011869:Radioligand Assay / Q000379:methods; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D014446:Tyrosine 3-Monooxygenase; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D004298:Dopamine