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

Abstract

Mutations in Pink1, a gene encoding a Ser͞Thr 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.mitochondria ͉ Parkinson's disease ͉ Pten-induced kinase 1 ͉ indirect flight muscle P arkinson's disease (PD) is the most common movement disorder characterized pathologically by the deficiency of brain dopamine content and the selective degeneration of dopaminergic neurons in the substantia nigra. The most common forms of PD are sporadic with no known cause. Nevertheless, postmortem studies have identified common features associated with sporadic PD, such as mitochondrial complex I dysfunction, oxidative stress, and aggregation of abnormal proteins (1, 2).Although initial studies on the etiology of PD have focused on environmental factors, recent genetic studies have firmly established the contribution of inheritable factors in PD pathogenesis (2, 3). At least ten distinct loci have been associated with rare familial forms of PD (FPD). It is anticipated that understanding the molecular lesions associated with these FPD genes will shed light on the pathogenesis of the more common forms of the disease. Dominant mutations in ␣-Synuclein (␣-Syn) and LRRK2͞dardarin and recessive mutations in parkin, DJ-1, and Pink1 have been associated with FPD (4-10). Of these five genes, ␣-Syn, parkin, and DJ-1 have been most intensively studied. Studies using in vivo animal models and in vitro cell culture have linked mutations of these genes to impairments of mitochondrial structure and function and oxidative stress response, reinforcing the general involvement of mitochondrial dysfunction and oxidative stress in PD pathogenesis (11-21). Consistent with this notion, these proteins have been shown to be present in mitochondria or interact with mitochondrial proteins (8,(22)(23)(24), suggesting that they may directly regulate mitochondria function.A further link between mitochondria and PD was supported by the fact that Pink1 encodes a predicted Se...

RBR Ubiquitin Ligases: Diversification and Streamlining in Animal Lineages

“…This difference may be due to the presence of CG12362, a recent duplicate of ariadne-1 (Marín and Ferrús 2002). On the other hand, parkin mutants are viable, although show some phenotype changes, caused by a general mitochondrial dysfunction (Greene et al 2003;Pesah et al 2004;Clark et al 2006;Park et al 2006;Yang et al 2006). For the other genes, there are no loss-offunction mutants described.…”

miR-484 regulates mitochondrial network through targeting Fis1

“…Strikingly, most recent studies reveal that abnormal mitochondrial fusion and fission participate in the regulation of apoptosis 5,6 . In particular, they are related to a variety of diseases such as skeletal muscle disorders [7][8][9] , peripheral neuropathy CharcotMarie-Tooth type 2A 10,11 and neurodegeneration 12 .…”

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…PINK1 mutants share many phenotypic features with parkin mutants [250,251]. Therefore, it was suggested that the two proteins could act in common pathways, with parkin working downstream of PINK1, because transgenic expression of parkin rescued all PINK1 impairments, but not the contrary [243,250,251].…”

“…Therefore, it was suggested that the two proteins could act in common pathways, with parkin working downstream of PINK1, because transgenic expression of parkin rescued all PINK1 impairments, but not the contrary [243,250,251]. Goldman et al [252] reported that PINK1 and parkin both play a role in the mitochondrial targeting of autophagy, a process by which the cells degrade intracellular material through lysosomes.…”