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. PubMed.
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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.
References:
Li YJ, Oliveira SA, Xu P, Martin ER, Stenger JE, Scherzer CR, Hauser MA, Scott WK, Small GW, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Goetz CG, Mastaglia F, Middleton LT, Roses AD, Saunders AM, Schmechel DE, Gullans SR, Haines JL, Gilbert JR, Vance JM, Pericak-Vance MA, Hulette C, Welsh-Bohmer KA. Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum Mol Genet. 2003 Dec 15;12(24):3259-67. PubMed.
View all comments by Jeffery VanceNational Institute on Aging
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.
References:
von Coelln R, Thomas B, Savitt JM, Lim KL, Sasaki M, Hess EJ, Dawson VL, Dawson TM. Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10744-9. PubMed.
Singh SP, Coronella JA, Benes H, Cochrane BJ, Zimniak P. Catalytic function of Drosophila melanogaster glutathione S-transferase DmGSTS1-1 (GST-2) in conjugation of lipid peroxidation end products. Eur J Biochem. 2001 May;268(10):2912-23. PubMed.
Shen J, Cookson MR. Mitochondria and dopamine: new insights into recessive parkinsonism. Neuron. 2004 Aug 5;43(3):301-4. PubMed.
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