4.2 Article

DJ-1-deficient mice show less TH-positive neurons in the ventral tegmental area and exhibit non-motoric behavioural impairments

期刊

GENES BRAIN AND BEHAVIOR
卷 9, 期 3, 页码 305-317

出版社

WILEY
DOI: 10.1111/j.1601-183X.2009.00559.x

关键词

Ageing; cognitive behaviour; gene trap; JNKs; mitochondrial complexes; oxidative stress; Parkinson's disease

资金

  1. Deutsche Forschungsgemeinschaft [SFB596]
  2. Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN) Forderkennzeichen [01GS0476, 01GR0430, 01GS08174, 01GN0512]
  3. Helmholtz Alliance 'Mental Health in an Ageing Society

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Loss of function of DJ-1 (PARK7) is associated with autosomal recessive early-onset Parkinson's disease (PD), one of the major age-related neurological diseases. In this study, we extended former studies on DJ-1 knockout mice by identifying subtle morphological and behavioural phenotypes. The DJ-1 gene trap-induced null mutants exhibit less dopamine-producing neurons in the ventral tegmental area (VTA). They also exhibit slight changes in behaviour, i.e. diminished rearing behaviour and impairments in object recognition. Furthermore, we detected subtle phenotypes, which suggest that these animals compensate for the loss of DJ-1. First, we found a significant upregulation of mitochondrial respiratory enzyme activities, a mechanism known to protect against oxidative stress. Second, a close to significant increase in c-Jun N-terminal kinase 1 phosphorylation in old DJ-1-deficient mice hints at a differential activation of neuronal cell survival pathways. Third, as no change in the density of tyrosine hydroxylase (TH)-positive terminals in the striatum was observed, the remaining dopamine-producing neurons likely compensate by increasing axonal sprouting. In summary, the present data suggest that DJ-1 is implicated in major non-motor symptoms of PD appearing in the early phases of the disease-such as subtle impairments in motivated behaviour and cognition-and that under basal conditions the loss of DJ-1 is compensated.

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