Dopaminergic cell damage and vulnerability to MPTP in Pink1 knockdown zebrafish

Abstract

The functions of PTEN (phosphatase/tensin homolog)-induced putative kinase (PINK1), which is mutated in early-onset Parkinson's disease, are poorly understood. We characterized a PINK1 antibody and found colocalization of PINK1-like immunoreactivity with aminergic markers. We inactivated translation of Pink1 using morpholino-oligonucleotides (MOs) in larval zebrafish. Dopaminergic neurons consisted of two sets of neuron populations, marked by complementary expression of two tyrosine hydroxylase genes th1 and th2. Translation inhibition of pink1 resulted in reduction of both th mRNA forms until day 5 or 7, respectively. The affected dopaminergic neurons were in one group expressing th1 and three groups expressing th2. Lack of Pink1 sensitized the fish to subeffective doses of MPTP, which caused a locomotor deficit and facilitated loss of th1 in one diencephalic dopaminergic cell group. Control experiments with pink1 mRNA and control MO suggested that effects with the splice site targeting MO were specific. Distinct groups of dopaminergic neurons are thus sensitive to loss of Pink1. Sensitization of the pink1 morphant fish to MPTP toxicity suggests that genetic factors play a role in toxin-induced Parkinson's disease.

Keywords

• Parkinson's disease
• Park6
• Neurodegeneration
• Tyrosine hydroxylase
• Dopamine
• Translation inhibition