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Glutathione peroxidase activity is neuroprotective in models of HD Nat Genet. 2013 Oct;45(10):1249-54. doi: 10.1038/ng.2732. Epub 2013 Aug 25. By: Mason RP, Casu M, Butler N, Breda C, Campesan S, Clapp J, Green EW, Dhulkhed D, Kyriacou CP, Giorgini F (Summary by Robert Mason, PhD and Flaviano Giorgini, PhD) Genetic modifiers of HD are a valuable source of potential therapeutic targets for this devastating disorder 1 . To uncover such modifiers we performed genetic screens in baker's yeast, and identified 317 genes whose increased expression led to reduced mHTT toxicity 2 . These modifiers are involved in a wide variety of cellular processes and include members of the glutathione peroxidase (GPx) family of antioxidant enzymes, which may help protect against the increase in oxidative stress observed in HD. Glutathione peroxidases are an exciting therapeutic target due to the availability of compounds that mimic their activity. These enzymes have been tested in humans for the treatment of stroke and noise-induced hearing loss, 3,4 possibly expediting translation into the clinic for HD patients. Notably, we found that increased levels of mouse GPX1, the most abundant mammalian glutathione peroxidase, or treatment with the GPx- mimicking compound ebselen, improved disease phenotypes in fruit fly and mammalian cell models of HD. Interestingly, increasing GPx activity was more protective than other antioxidant strategies. Unlike other antioxidant strategies, increasing GPx activity does not inhibit autophagy, an important process for the clearance of mHTT from the cell, which may contribute to the differences in protection observed. Future studies seek to evaluate the efficacy of increasing GPx activity in animal models of HD, providing critical validation before pursuing this novel candidate therapeutic approach in patients. Copyright © Huntington Study Group 2014. All rights reserved. 1 Gusella JF, MacDonald ME, Lee JM. Genetic modifiers of Huntington's disease. Mov Disord. 2014 Sep 15;29(11):1359-65. doi: 10.1002/mds.26001. Epub 2014 Aug 25. 2 Mason RP, Casu M, Butler N, Breda C, et al. Glutathione peroxidase activity is neuroprotective in models of Huntington's disease. Nat Genet. 2013 Oct;45(10):1249-54. doi: 10.1038/ng. 2732. Epub 2013 Aug 25. 3 Day, B.J. Catalase and glutathione peroxidase mimics. Biochem Pharmacol. 2009 Feb 1;77(3): 285–296. 4 Lynch ED, Kil J. Compounds for the prevention and treatment of noise-induced hearing loss. Drug Discov Today. 2005 Oct 1;10(19):1291-8. Research Round-Up: Insights, cont... Image: Glutathione peroxidases protect the cell from oxidative stress by detoxifying hydrogen peroxide, which can cause oxidative stress through the production of harmful free radicals. Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons Nat Neurosci. 2014 Aug;17(8):1064-72. doi: 10.1038/nn.3761. Epub 2014 Jul 13. By: Pecho-Vrieseling E, Rieker C, Fuchs S, Bleckmann D, Esposito MS, Botta P, Goldstein C, Bernhard M, Galimberti I, Müller M, Lüthi A, Arber S, Bouwmeester T, van der Putten H, Di Giorgio FP (Summary by Lise Munsie, PhD) This thorough study demonstrates the transneuronal spreading of mHTT that may contribute to non-cell autonomous neuropathology. The authors cultured human neurons from embryonic stem cells and seeded them in organotypic brain slices from the R6/2 mouse model. They subsequently found that mHTT aggregates accumulate in human neurons, leading to pathological consequences for these neurons. These results were recapitulated in vivo in the mouse model. The cortico- striatal pathway was examined using mixed-genotype cortico-striatal brain slice cultures from R6/2 mice and their wild- type counterparts. The authors found that mHTT can spread in a pre- to post-synaptic manner, as they found aggregates in wild-type medium spiny neurons after culturing with R6/2 cortex, but not the other way around. Finally, the authors used endoproteases that cleave part of the synaptic vesicle docking fusion SNARE complex, to show that this spread is mediated through synaptic vesicle recycling. The endoproteases used cleave SNAP25 and VAMP. Both treatments significantly reduced the spread of mHTT in their model. H D I N S I G H T S HD Insights, Vol. 9 4