Issue link: http://www.e-digitaleditions.com/i/399268
Research Round-Up: Insights of the Year 2013-2014 Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of HD Nat Med. 2014 May;20(5):536-41. doi: 10.1038/nm.3514. Epub 2014 Apr 28. 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) We 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. Copyright © Huntington Study Group 2014. All rights reserved. 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! Image: Labeling of mouse cortical pyramidal neurons (green), striatal medium spiny neurons (purple,) and of all other neurons throughout the brain (red). Most influential paper In the lab… 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. H D I N S I G H T S HD Insights, Vol. 9 3