Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter.
Mutations in the gene for DJ-1 have been associated with early-onset autosomal recessive parkinsonism. Previous studies of null DJ-1 mice have shown alterations in striatal dopamine (DA) transmission with no DAergic cell loss. Here we characterize a new line of DJ-1-deficient mice. A subtle locomotor deficit was present in the absence of a change in striatal DA levels. However, increased [(3)H]-DA synaptosomal uptake and [(125)I]-RTI-121 binding were measured in null DJ-1 vs. wild-type mice. Western analyses of synaptosomes revealed significantly higher dopamine transporter (DAT) levels in pre-synaptic membrane fractions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure exacerbated striatal DA depletion in null DJ-1 mice with no difference in DAergic nigral cell loss. Furthermore, increased 1-methyl-4-phenylpyridinium (MPP(+)) synaptosomal uptake and enhanced MPP(+) accumulation were measured in DJ-1-deficient vs. control striatum. Thus, under null DJ-1 conditions, DAT changes likely contribute to altered DA neurotransmission and enhanced sensitivity to toxins that utilize DAT for nigrostriatal entry.
Manning-Boğ
Amy B
AB
Department of Basic Research, The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089, USA. amanning-bog@thepi.org
Caudle
W Michael
WM
Perez
Xiomara A
XA
Reaney
Stephen H
SH
Paletzki
Ronald
R
Isla
Martha Z
MZ
Chou
Vivian P
VP
McCormack
Alison L
AL
Miller
Gary W
GW
Langston
J William
JW
Gerfen
Charles R
CR
Dimonte
Donato A
DA
D000818:Animals; D015153:Blotting, Western; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D020267:MPTP Poisoning; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D015513:Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D054464:Peroxiredoxins; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology; D000071617:Protein Deglycase DJ-1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D013574:Synaptosomes / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D015513:Oncogene Proteins; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D004298:Dopamine