Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter

Neurobiol Dis. 2007 Aug;27(2):141-50. doi: 10.1016/j.nbd.2007.03.014. Epub 2007 May 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Immunohistochemistry
  • MPTP Poisoning
  • Mice
  • Mice, Transgenic*
  • Motor Activity / physiology
  • Oncogene Proteins / deficiency*
  • Oncogene Proteins / genetics
  • Peroxiredoxins
  • Presynaptic Terminals / metabolism*
  • Presynaptic Terminals / pathology
  • Protein Deglycase DJ-1
  • Reverse Transcriptase Polymerase Chain Reaction
  • Substantia Nigra / metabolism*
  • Substantia Nigra / pathology
  • Synaptosomes / metabolism

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Oncogene Proteins
  • Peroxiredoxins
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1
  • Dopamine