POMD08 Zebrafish models for early onset Parkinson's disease

Zebrafish are a vertebrate animal model system which is highly amenable for drug screens. Autosomal recessively inherited, loss of function mutations in the PTEN-induced kinase 1 (pink1) gene are one cause of early-onset Parkinson's disease (PD). Objectives (1) To establish a stable pink1 mutant zebrafish line and determine whether this pink1 mutant line shares crucial characteristics with human pink1-mutant patients, in particular loss of dopaminergic neurones and impaired mitochondrial function. (2) To further elucidate mechanisms leading to impaired mitochondrial function and neuronal cell death in early onset PD. Findings We screened several libraries of ENU-mutagenised fish using primers corresponding to all eight exons of pink1, and found a single founder with a stop mutation in exon 7 (Y431*). Adult pink1-/- fish do not display any overt behavioural abnormalities. Pink1-/- embryos at 5 days postfertilisation (dpf) have a significant (p<0.05) decrease in the number of TH+ cells and reduction in mitochondrial complex I activity. Eight of 21 genes down-regulated in pink1 -/- embryos are involved in energy production, mitochondrial function or oxidative stress response. Conclusion Our results suggest these pink1-/- zebrafish may be a useful tool for studying the pathogenesis of early-onset PD, and could also be used in small molecule screens to identify new drug targets.