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Keywords:

  • parkin knockout;
  • Parkinson's disease

Abstract

Mutations in the parkin gene are the major cause of early-onset familial Parkinson's disease (PD). We previously reported the generation and analysis of a knockout mouse carrying a deletion of exon 3 in the parkin gene. F1 hybrid pa+/– mice were backcrossed to wild-type C57Bl/6 for three more generations to establish a pa–/–(F4) mouse line. The appearance of tyrosine hydroxylase-positive neurons was normal in young and aged pa–/– (F4) animals. Loss of parkin function in mice did not enhance vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. However, the pa–/– (F4) mice displayed impaired exploration and habituation to a new environment and exhibited thigmotaxis behaviour in the open field and Morris water maze. Abnormal anxiety-related behaviour of pa–/– (F4) mice was also observed in the light/dark exploration test paradigm. Dopamine metabolism was enhanced in the striatum of pa–/– (F4) mice, as revealed by increased homovanillic acid (HVA) content and a reduced ratio of dihydroxyphenylacetic acid (DOPAC)/HVA. The alterations found in the dopaminergic system could be responsible for the behavioural impairments of pa–/– (F4) mice. Consistent with a recent observation of cognitive dysfunction in parkin-linked patients with PD, our findings provide evidence of a physiological role of parkin in non-motor behaviour, possibly representing a disease stage that precedes dopaminergic neuron loss.