POMD08 Zebrafish models for early onset Parkinson's disease

Abstract

BackgroundZebrafish 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.FindingsWe 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.ConclusionOur 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.

Molecular Mechanisms of PINK1-Related Neurodegeneration

“…A later model corroborated these findings, as well as noting weight loss and a mild movement deficit [23]. Additional PINK1 mutant models have been produced in Caenorhabditis elegans, where increased susceptibility to oxidative stress and mitochondrial morphology defects were observed [24], as well as in Danio rerio, which exhibit a decrease in dopamine-producing cells and reduced mitochondrial activity [25].…”

In vivo imaging of small animal models by photoacoustic microscopy

“…In addition, they can implement large-scale gene mutation and screening. These features make small animal models important in life science researches in the study of functional genomics era [2][3][4].…”

Mitophagy and neurodegeneration

“…In order to determine if this is indeed the case, stable knockout lines of both pink1 and park2 are required. Bandmann et al 121 have reported the discovery of a pink1 mutant by TILLING. This mutant has a premature stop codon in exon 7 (Y431X).…”

“…This suggests that Gsk3b may play a role in the peripheral phenotypes observed, but that other factors are involved in the dopamine neuron loss. Further study of Wnt signaling, the known pink1 mutant 121 and generation of another pink1 knockout model is therefore recommended.…”