Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of <i>Drosophila</i> Pink1 is rescued by Parkin

TLDR

Mutations in the mitochondrial kinase Pink1 are linked to Parkinson’s disease, a movement disorder marked by selective loss of dopaminergic neurons, yet the mechanism by which Pink1 loss causes neurodegeneration remains unclear. Loss of Drosophila Pink1 causes energy depletion, shortened lifespan, and degeneration of flight muscles and dopaminergic neurons, with mitochondrial enlargement preceding the pathology, and these defects are rescued by wild‑type human Pink1 or Parkin overexpression but not by a C‑terminal deleted Pink1 or DJ‑1, indicating that Pink1 and Parkin act in a shared mitochondrial pathway essential for cell survival.

Abstract

Mutations in Pink1, a gene encoding a Ser/Thr kinase with a mitochondrial-targeting signal, are associated with Parkinson's disease (PD), the most common movement disorder characterized by selective loss of dopaminergic neurons. The mechanism by which loss of Pink1 leads to neurodegeneration is not understood. Here we show that inhibition of Drosophila Pink1 (dPink1) function results in energy depletion, shortened lifespan, and degeneration of select indirect flight muscles and dopaminergic neurons. The muscle pathology was preceded by mitochondrial enlargement and disintegration. These phenotypes could be rescued by the wild type but not the pathogenic C-terminal deleted form of human Pink1 (hPink1). The muscle and dopaminergic phenotypes associated with dPink1 inactivation show similarity to that seen in parkin mutant flies and could be suppressed by the overexpression of Parkin but not DJ-1. Consistent with the genetic rescue results, we find that, in dPink1 RNA interference (RNAi) animals, the level of Parkin protein is significantly reduced. Together, these results implicate Pink1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in Drosophila.