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Search and Rescue in Parkin Fly Mutants—DA Neurons Are Lost, but Saved by GST
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27 May 2005. Two years ago, Leo Pallanck and Mel Feany and their colleagues succeeded in breeding fruit flies with mutations in parkin, the gene responsible for most cases of early-onset PD in humans (see ARF related news story). To the disappointment of many, those flies did not seem to fully recapitulate the quintessential feature of PD, namely the gradual loss of dopaminergic neurons in the brain. Now, search-and-rescue experiments by Pallanck and colleagues at the University of Washington in Seattle reveal that parkin mutants do, in fact, suffer a subtle and progressive loss of a single subset of those neurons. What’s more, the authors have found a way to prevent that loss—increasing expression of the antioxidant enzyme glutathione S-transferase (GST).
The work, which appears online this week in PNAS, indicates that oxidative stress, long thought to cause sporadic PD in humans, can wipe out dopaminergic neurons in parkin flies, as well. The results raise the hope that antioxidants, and in particular therapies that boost GST, could offer a new advance for PD treatment. This view is in sync with a recent meta-analysis of dietary studies, which suggests that eating foods rich in vitamin E can reduce the risk of PD.
Drosophila parkin mutants, like their human counterparts, suffer from mitochondrial dysfunction, but the most obvious ramification for flies turned out to be muscle wasting, not neuronal loss. The less obvious neuronal phenotype was revealed only when the researchers, led by first author Alexander Whitworth, performed tyrosine hydroxylase staining and confocal microscopy on whole brains to look at every single dopaminergic (DA) neuron. By visualizing individual neurons, Whitworth was able to pick up one neuronal cluster—out of the dozen or so present in flies—that in mutant animals showed a significant, age-related reduction in DA neurons. Apart from that, the flies showed no gross brain abnormality and no defects in other neurons. Whitworth and colleagues found that the pinpoint lesion, occurring in the protocerebral posterior lateral (PPL1) cluster, was due to parkin deficiency, because enforced expression of parkin in the DA neurons restored that cluster.
Having identified a DA neuron loss phenotype, the researchers then screened for additional mutants that could modify the parkin effect. The strongest enhancers they found were loss-of function mutations in the Drosophila GST1 gene. Even 1-day-old parkin flies with GST1 mutations had significantly enhanced PPL1 neuron loss, while the same mutations had no effect on normal flies. Expression of GST1 targeted to DA neurons in the parkin mutants prevented neuronal loss, comparable to the level of rescue seen with parkin overexpression. GST expression driven by a muscle-specific promoter also prevented degeneration in that tissue.
From these results, the authors propose that parkin functions to protect neurons and other tissues from oxidative stress and its resulting tissue damage. They saw direct evidence for oxidative damage in the parkin flies, which had 4 times higher levels of protein carbonyls than usual. The next step will be figuring out how parkin protects cells, whether by getting rid of damaged proteins, by affecting mitochondrial integrity, or maybe even by targeting malfunctioning mitochondria for destruction, the authors speculate.
In humans, a large body of evidence links oxidative stress to both early-onset and sporadic PD. Alleles of the human omega-1 GST gene influence the onset of sporadic PD (Li et al., 2004). While the flies may not be a perfect model for human PD (they lack homologs of important parkin substrates, for one thing), the striking similarities between flies and people in this study suggest that pharmacologic elevation of GST should be considered as a new approach to PD therapy.
Of course, the use of antioxidants, and particularly antioxidant vitamins, to stave off all manner of aging-related diseases is not a new principle. A meta-analysis of eight separate dietary studies looking at vitamin E and ascorbic acid, or vitamin C, concludes that moderate dietary intake of vitamin E, but not the other nutrients, is associated with a reduced risk of PD. The study, led by Mahyar Etminan of McGill University in Montreal and published in the June Lancet Neurology, looked only at vitamin E intake in food and not supplements, which have been shown to give no protection against PD (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=8417384&dopt=Abstract) or AD (see ARF related news story) in prospective placebo-controlled clinical trials. So rather than pop that pill, perhaps we’d best just eat our fruits and vegetables.—Pat McCaffrey.
References:
Whitworth AJ, Theodore DA, Greene JC, Benes H, Wes PD, Pallanck LJ. Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc Natl Acad Sci U S A. 2005 May 31;102(22):8024-9. Epub 2005 May 23. Abstract
Etminan M, Gill SS, Samii A. Intake of vitamin E, vitamin C, and carotenoids and the risk of Parkinson's disease: a meta-analysis. Lancet Neurol. 2005 Jun;4(6):362-5. Abstract
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Comments on News and Primary Papers |
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Comment by: Jeffery Vance
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Submitted 27 May 2005
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Posted 27 May 2005
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Genes that affect the severity, duration, and course of Parkinson disease (PD) are just beginning to be explored. They are very important not only to understanding of the disease, but may provide the best opportunities to develop new treatments for PD. After all, most drugs we take now for any medical problem primarily modify the course of the disease (shorten it, make it less severe, etc.). In addition, while we now know that PD is not just one disease, but has many causes, those diseases all seem to produce the same basic symptoms. This suggests that no matter what the cause of PD, at some point they must “merge” and begin to interfere with the same areas of the brain. With the addition of this exciting paper, the glutathione S-transferases (GST) group of enzymes have now been shown to modify disease that was caused by three different phenomena and in three different organisms: Parkin mutations in a PD fly model as reported in this paper, α-synuclein defects in a yeast model, and actual “idiopathic” PD in human patients by our own group, with recent work showing that variations...
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Genes that affect the severity, duration, and course of Parkinson disease (PD) are just beginning to be explored. They are very important not only to understanding of the disease, but may provide the best opportunities to develop new treatments for PD. After all, most drugs we take now for any medical problem primarily modify the course of the disease (shorten it, make it less severe, etc.). In addition, while we now know that PD is not just one disease, but has many causes, those diseases all seem to produce the same basic symptoms. This suggests that no matter what the cause of PD, at some point they must “merge” and begin to interfere with the same areas of the brain. With the addition of this exciting paper, the glutathione S-transferases (GST) group of enzymes have now been shown to modify disease that was caused by three different phenomena and in three different organisms: Parkin mutations in a PD fly model as reported in this paper, α-synuclein defects in a yeast model, and actual “idiopathic” PD in human patients by our own group, with recent work showing that variations in GST-omega can affect age at onset of PD by as much as 7 to 8 years alone (see Li et al., 2003). Thus, this paper is important not only because it begins to connect many different findings in PD research over the last few years, but it also strongly supports that the GST enzymes are important modifiers of the course of PD, are likely to affect most patients, no matter what the cause of the disease, and certainly should be a focus of therapeutic efforts in PD.
 View all comments by Jeffery Vance |
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Comment by: Mark Cookson
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Submitted 2 June 2005
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Posted 2 June 2005
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The main novel observation in this very exciting paper from Whitworth and colleagues is that there is a subtle loss of catecholaminergic neurons in parkin knockout flies. Mouse models have generally not found any loss of dopaminergic neurons, although a report from the Dawson laboratory did show neuronal loss in the locus coeruleus ( Von Coelln et al., 2004). I don’t know if there is any relationship between the LC in the mice and the PPL1 neuronal group in Drosophila, but it’s striking that there are very subtle losses in very small subsets of neurons.
The other major observation is that GST-S1 prevents neuronal loss in the same model. GST-S1 has been shown to detoxify oxidized lipid conjugates in the fly and is highly expressed in the nervous system and in aerobic muscles (Singh et al., 2001). How would this activity prevent neuronal damage resulting from loss of parkin? It is possible that GST activity protects downstream of a general oxidative stress resulting from parkin...
Read more
The main novel observation in this very exciting paper from Whitworth and colleagues is that there is a subtle loss of catecholaminergic neurons in parkin knockout flies. Mouse models have generally not found any loss of dopaminergic neurons, although a report from the Dawson laboratory did show neuronal loss in the locus coeruleus ( Von Coelln et al., 2004). I don’t know if there is any relationship between the LC in the mice and the PPL1 neuronal group in Drosophila, but it’s striking that there are very subtle losses in very small subsets of neurons.
The other major observation is that GST-S1 prevents neuronal loss in the same model. GST-S1 has been shown to detoxify oxidized lipid conjugates in the fly and is highly expressed in the nervous system and in aerobic muscles (Singh et al., 2001). How would this activity prevent neuronal damage resulting from loss of parkin? It is possible that GST activity protects downstream of a general oxidative stress resulting from parkin deficiency, occurring via mitochondrial damage. If this was the case, one might expect other antioxidants to be helpful, as well. It is also possible that GST has a more specific role than merely shoring up defenses in neurons, some of which are discussed in the Whitworth et al. paper. These are attractive ideas, but don’t completely explain why a ubiquitin-protein ligase would affect mitochondrial and oxidative stress pathways, a mystery that has been noted before (Shen and Cookson, 2004). Clearly, there are several things about parkin that we still don’t quite understand and that need to be resolved before we can fully appreciate some of these recent results.
Very speculatively, it’s worth noting that other recessive genes associated with parkinsonism might also be involved in the same pathway(s). DJ-1 is implicated in resistance to oxidative stress and appears to be loosely associated with mitochondria, although that data is not completely resolved yet. PINK1 is definitely imported into the mitochondria and, as a kinase, has the potential to contribute to pro-cell survival signaling pathways. An experiment to see if either of these two genes (but not inactive variants) would protect against the phenotypes found by Whitworth et al. might start to disentangle whether or not we are looking at one disease process in these different genetic disorders.
View all comments by Mark Cookson |
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