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HD InsightsResearch Round-Up: Insights of the Year 2013-2014 (In the Lab)

In our final issue for 2014, the HD Insights team wanted to recognize the most influential papers in HD research in the 2013–2014 year. Our staff, Editorial Board, and leading HD researchers nominated the eleven papers below in three categories: lab research, clinical research, and imaging and biomarkers. The HD Insights Editorial Board then voted to select the three most influential papers, one in each category. The authors of the winning papers will present their research in a panel discussion at the Huntington Study Group meeting on November 7, 2014. Congratulations to all the nominees and winners!

Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of HD

 By: Wang N, Gray M, Lu XH, Cantle JP, Holley SM, Greiner E, Gu X, Shirasaki D, Cepeda C, Li Y, Dong H, Levine MS, Yang XW (Summary by X. William Yang, MD, PhD)

Nat Med. 2014 May; 20(5):536-41. doi: 10.1038/nm.3514. Epub 2014 Apr 28. 

imageWe developed a conditional transgenic mouse model of HD (BACHD) to address the question of how ubiquitously expressed mutant huntingtin (mHTT) may selectively target striatal and cortical neurons for degeneration. The model expresses full-length human mHTT from a genomic transgene that confers endogenous-like mHTT expression patterns. The expression of mHTT in BACHD mice can be genetically shut off in cells that express Cre recombinase, allowing researchers to precisely assess the role of mHTT that is synthesized in one cell type or a combination of cell types in disease pathogenesis. Our study showed that genetically reducing mHTT in cortical neurons significantly ameliorates psychiatric-like behavioral deficits, modestly improves motor impairment, but does not improve neurodegeneration.

Importantly, we found that reducing mHTT in both cortical and striatal neurons, but not in either neuronal population alone, consistently improves all the behavioral deficits and selective brain atrophy in this HD mouse model. The study also showed that striatal synaptic dysfunction in BACHD requires both non– cell-autonomous and cell-autonomous toxicities, from cortical and striatal neurons respectively. Together, our study demonstrated distinct but interacting roles of cortical and striatal mHTT in HD pathogenesis, and suggests that optimal HD therapeutics may require targeting mHTT in both cortical and striatal neurons.

Glutathione peroxidase activity is neuroprotective in models of HD

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)

Nat Genet. 2013 Oct;45(10):1249-54. doi: 10.1038/ng.2732. Epub 2013 Aug 25.

image 2Genetic modifiers of HD are a valuable source of potential therapeutic targets for this devastating disorder1. To uncover such modifiers we performed genetic screens in baker’s yeast, and identified 317 genes whose increased expression led to reduced mHTT toxicity2. 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.

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 Oct1;10(19):1291-8.

Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons

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)

Nat Neurosci. 2014 Aug;17(8):1064-72. doi: 10.1038/nn.3761. Epub 2014 Jul 13.

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.

Inhibition of mitochondrial protein import by mutant huntingtin

By: Yano H, Baranov SV, Baranova OV, Kim J, Pan Y, Yablonska S, Carlisle DL, Ferrante RJ, Kim AH, Friedlander RM.! (Summary by Lise Munsie, PhD)

Nat Neurosci. 2014 Jun; 17(6):822-31. doi: 10.1038/nn.3721. Epub 2014 May 18.

Mitochondrial dysfunction is intimately involved in the progression of HD; however, the mechanism of this dysfunction is unknown. Robert Friedlander’s group explored this in a recent Nature Neuroscience paper. Initially, the authors found that mHTT is specifically localized to mitochondria in brains from HD patients and also mouse models. Unbiased protein identification from immunoprecipitation shows that mHTT binds members of the TIM23 complex, a complex that imports matrix proteins into the inner mitochondrial membrane. Using in vitro mitochondrial protein assays, the group demonstrated that the N-terminus of mHTT is involved in this aberrant binding, leading to decreased mitochondrial protein import. This defect is enhanced in mitochondria purified from synaptosomes, compared to mitochondria purified from other parts of the cell or other cell types. The group showed that the mitochondrial protein import dysfunction is a mHTT specific function and not mediated through the polyglutamine expansion alone, and thus is a mechanism specific to HD. They additionally showed that altering protein import to the mitochondria is neurotoxic and that overexpressing major subunits of the TIM23 complex can rescue mHTT-induced neurotoxicity.


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Our mission is to promote, disseminate, and facilitate research on Huntington’s disease. To fulfill this mission, we are guided by an outstanding editorial board that includes representatives from three continents, academia, industry, and the HD community.