Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Several lines of evidence strongly implicate mitochondrial dysfunction as a major causative factor in PD, although the molecular mechanisms responsible for mitochondrial dysfunction are poorly understood. Recently, loss-of-function mutations in the parkin gene, which encodes a ubiquitin-protein ligase, were found to underlie a familial form of PD known as autosomal recessive juvenile parkinsonism (AR-JP). To gain insight into the molecular mechanism responsible for selective cell death in AR-JP, we have created a Drosophila model of this disorder. Drosophila parkin null mutants exhibit reduced lifespan, locomotor defects, and male sterility. The locomotor defects derive from apoptotic cell death of muscle subsets, whereas the male sterile phenotype derives from a spermatid individualization defect at a late stage of spermatogenesis. Mitochondrial pathology is the earliest manifestation of muscle degeneration and a prominent characteristic of individualizing spermatids in parkin mutants. These results indicate that the tissue-specific phenotypes observed in Drosophila parkin mutants result from mitochondrial dysfunction and raise the possibility that similar mitochondrial impairment triggers the selective cell loss observed in AR-JP. P arkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of proteinaceous intraneuronal inclusions known as Lewy bodies. Little is known of the molecular mechanisms responsible for loss of dopaminergic neurons in PD; however, evidence suggests that environmental and genetic factors both play contributing roles (1-3). Although only a few of the factors contributing to this disorder have currently been identified, significant insight into the mechanism of neuronal death in PD has come from studies of the PD-inducing compound 1-methyl-4-phenylpyridinium (MPP ϩ ). MPP ϩ is a specific toxin of dopaminergic neurons that induces cell death by inhibiting mitochondrial complex I (4-6). This finding led to the identification of other mitochondrial complex I inhibitors that trigger death of dopaminergic neurons (7,8), and prompted studies of mitochondrial integrity in individuals with idiopathic PD (9-13). These studies revealed a correlation between PD and mitochondrial dysfunction, and together with the studies of mitochondrial toxins, provide strong support for mitochondrial dysfunction as a major component of PD.Although mitochondrial dysfunction appears to be a prominent feature of idiopathic PD, the molecular mechanisms responsible for mitochondrial dysfunction remain largely unknown. Insight into the molecular mechanisms of neurodegeneration in PD is beginning to emerge from the identification of loci responsible for rare monogenic forms of this disorder. One of the genes identified from this work is parkin. Loss-of-function mutations in pa...

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

“…In PD, identification of disease-specific genes that influence mitochondrial physiology, either directly or indirectly, have contributed greatly to our understanding of the role of mitochondrial impairment in the etiology of this disease [1,2]. For example, mitochondrial pathology and oxidative stress are prominent in Drosophila parkin null mutants, and are associated with degeneration of a subset of dopaminergic neurons in the brain [11,60,61]. Although nigral degeneration is absent in parkin-deficient mice, they exhibit decreased striatal mitochondrial respiratory capacity and decreased levels of proteins involved in protection from oxidative stress [12].…”

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

“…Changes in mitochondrial morphologyhave been also observed, but this led only to disruption of complex I function in nigral mitochondria and did not result in cell death [233]. Thus, mitochondrial defects and an increased susceptibility to oxygen radical damage were also reported in a parkin knockout model of Drosophila, suggesting that abnormalities in parkin ubiquitination function might be secondary in the course of pathogenic events [234,235]. In vitro studies of PARK2Ͳknockdown SHͲSY5Y neuroblastoma cell line showed apoptotic cell death and high levels of autoxidized forms of LͲ DOPA and dopamine, suggesting that parkin might have important antioxidant properties [236].…”

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.…”