Increased glutathione S -transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease

Abstract

Loss-of-function mutations of the parkin gene are a major cause of early-onset parkinsonism. To explore the mechanism by which loss of parkin function results in neurodegeneration, we are using a genetic approach in Drosophila. Here, we show that Drosophila parkin mutants display degeneration of a subset of dopaminergic (DA) neurons in the brain. The neurodegenerative phenotype of parkin mutants is enhanced by loss-of-function mutations of the glutathione S-transferase S1 (GstS1) gene, which were identified in an unbiased genetic screen for genes that modify parkin phenotypes. Furthermore, overexpression of GstS1 in DA neurons suppresses neurodegeneration in parkin mutants. Given the previous evidence for altered glutathione metabolism and oxidative stress in sporadic Parkinson's disease (PD), these data suggest that the mechanism of DA neuron loss in Drosophila parkin mutants is similar to the mechanisms underlying sporadic PD. Moreover, these findings identify a potential therapeutic approach in treating PD.genetic modifier ͉ neurodegeneration ͉ parkin P arkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and the accumulation of proteinaceous intraneuronal inclusions known as Lewy bodies. The mechanisms responsible for neurodegeneration in PD are largely unknown, although previous work suggests that mitochondrial complex I dysfunction, oxidative stress, and aberrant proteolytic degradation may contribute to pathogenesis (1). The recent identification of genes responsible for rare inherited forms of parkinsonism presents an opportunity to establish neurodegenerative mechanisms that may be relevant to sporadic forms of PD.Loss-of-function mutations of parkin are a common cause of autosomal recessive juvenile parkinsonism (ARJP), and parkin dysfunction may also contribute to late-onset sporadic PD (2-6). Patients with parkin mutations display many of the typical features of idiopathic PD, including locomotor dysfunction, reduced mitochondrial complex I activity, and degeneration of DA neurons in the substantia nigra. However, most ARJP cases have a significantly earlier age of onset and lack Lewy body pathology. Parkin has been shown to possess ubiquitin-protein ligase activity (7-9), which acts to confer substrate target specificity in the ubiquitin͞proteasome protein degradation pathway. This finding has led to the model that toxic accumulation of parkin substrates may be responsible for DA neuron death. A number of putative substrates of parkin have been identified (10). Several of these parkin substrates, including the Lewy body component ␣-synuclein (11) and the putative G protein-coupled receptor Pael-R (12), have received considerable attention, in part because they implicate specific cellular pathways in parkinmediated pathogenesis. However, the involvement of many of the identified parkin substrates in the etiology of ARJP remains controversial.To identify pathways relevant to parkin pathogenesis, we are using a gen...

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

“…We noticed the similarity between our dPink1 RNAi flies and parkin mutant flies in the muscle and dopaminergic pathology (12,30,31). This observation prompted us to investigate whether Parkin and Pink1 might be involved in common physiological processes.…”

Alternative mutations of a positively selected residue elicit gain or loss of functionalities in enzyme evolution

“…For example, human GST M2-2 has prominent activity with orthoquinones such as aminochrome, formed from catecholamines, and their conjugation with glutathione has been proposed as a protective device against development of Parkinson's disease and other neurodegenerative conditions (14). In support of this notion, a Drosophila model of Parkinson's disease shows rescue of Parkin-defective dopaminergic neurons by GST expression (15). The high catalytic efficiency with orthoquinones is unique in humans to GST M2-2, and it can be argued that the acquisition of activity with novel substrates, such as epoxides, at the expense of the high activity with orthoquinones would be counterproductive.…”

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].…”