title: DJ-1-deficient mice show less TH-positive neurons in the ventral tegmental area and exhibit non-motoric behavioural impairments.
abstract: 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.
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter, Neuherberg, Germany.
authors.forename: T T
authors.initials: TT
authors.lastname: Pham
authors.forename: F
authors.initials: F
authors.lastname: Giesert
authors.forename: A
authors.initials: A
authors.lastname: Röthig
authors.forename: T
authors.initials: T
authors.lastname: Floss
authors.forename: M
authors.initials: M
authors.lastname: Kallnik
authors.forename: K
authors.initials: K
authors.lastname: Weindl
authors.forename: S M
authors.initials: SM
authors.lastname: Hölter
authors.forename: U
authors.initials: U
authors.lastname: Ahting
authors.forename: H
authors.initials: H
authors.lastname: Prokisch
authors.forename: L
authors.initials: L
authors.lastname: Becker
authors.forename: T
authors.initials: T
authors.lastname: Klopstock
authors.forename: M
authors.initials: M
authors.lastname: Hrabé de Angelis
authors.forename: K
authors.initials: K
authors.lastname: Beyer
authors.forename: K
authors.initials: K
authors.lastname: Görner
authors.forename: P J
authors.initials: PJ
authors.lastname: Kahle
authors.forename: D M
authors.initials: DM
authors.lastname: Vogt Weisenhorn
authors.forename: W
authors.initials: W
authors.lastname: Wurst
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005838:Genotype; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D054464:Peroxiredoxins; D010766:Phosphorylation / Q000235:genetics; D000071617:Protein Deglycase DJ-1; D021641:Recognition, Psychology / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D017557:Ventral Tegmental Area / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; D054464:Peroxiredoxins; D014446:Tyrosine 3-Monooxygenase; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D004298:Dopamine