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Research Round-Up By: Lise Munsie, PhD In the clinic... The globus pallidus (GP) is thought to be involved in cognitive processes controlling actions, and thus is a possible target for deep brain stimulation (DBS) in HD patients. Beste and colleagues 1 report a case- control study of patients who received GP- DBS, and measured patients' error monitoring processing, an output mediated by the basal ganglia known to be altered in HD. The preliminary results suggest that the GP-DBS is safe in this population and yields positive results with respect to cognitive function. In the past decade, transplantation of fetal striatal tissue into HD patients has emerged as an experimental treatment; however, recent evidence suggests that mutant huntingtin (mHTT) has the ability to spread between cells. Cicchetti and colleagues 2 examined intracerebral allografts transplanted into patients approximately one decade ago, who subsequently died secondary to HD progression. The results showed mHTT aggregates in the extracellular matrix of the donor tissue, suggesting that mHTT has the ability to spread, and supporting non-cell autonomous effects of mHTT. How mHTT spreads will be the subject of further study. Finally, PREDICT-HD has released their report on a decade-long trial that uses longitudinal data from premanifest HD individuals, reporting on biomarker and clinical progression assessments. 3 This work has documented 39 different variables, 36 of which show changes that can be measured between premanifest and control individuals, and will inform the design of future clinical trials for treatments aimed at individuals with premanifest HD. In the neurons… Huntingtin (HTT) has been shown to be functionally involved in aspects of axonal transport, and researchers are exploring axonal physiology and transport as functional targets for drug discovery in HD. Smith and colleagues 4 report on their new heterozygous knock-in mouse model of HD, which recapitulates motor deficits, inclusion formation and decreased striatal volume in HD. Synaptic, cytoskeletal and axonal transport proteins such as kinesin, dynein, and dynactin are altered in this mouse model prior to neurodegeneration, suggesting that the proteins may be a good target for presymptomatic drug discovery. Marangoni and colleagues 5 use HD mouse models crossed with YFP-H transgenic mice, which express the fluorescent marker protein YFP in a subset of neurons, to investigate axon pathology and examine axonal swelling in relation to HD progression. Interestingly, age-dependent axonal swelling was evident in a full-length homozygous knock-in Hdh Q140 model, but not in the widely used transgenic hemizygous R6/2 model. This axonal swelling did not correlate with aggregate formation, indicating that soluble mHTT may affect axons and axonal transport. Finally, Wong and Holzbaur 6 report on HTT and HAP1 involvement in axonal transport of autophagasomes in LC3-GFP mice. By live-cell imaging they demonstrate that mHTT causes a defect in axonal autophagasome transport, leading to inefficient degradative functions. The role of HTT and HAP1 in axonal transport seems to be mediated by binding to motor axonal proteins such as dynein, kinesin, and dynactin. This decreased degradative capacity leads to an increase in accumulation of mitochondrial fragments. In the genes... Gene knockdown and silencing are powerful tools for scientific discovery and leading possibilities for HD therapy. In a recent Nature Medicine report, 7 Wang and colleagues describe their use of the cre- recombinase system to selectively knock down mutant huntingtin (mHTT) in brain- specific regions in a full-length, floxed-exon 1 BACHD mouse model. They found that lowering mHTT in striatal neurons alone does not ameliorate all phenotypes, and that cortical knockdown of mHTT has consequences for striatal synaptic pathologies. This confirms the non-cell autonomous role of HTT and shows that HTT-lowering strategies in multiple brain regions will be needed. Drouet and colleagues 8 examined the use of short hairpin RNA (shRNA) targeting single nucleotide polymorphisms (SNPs) specific to the mHTT allele. Their shRNA platform that targets SNPs in exons 39, 50, 60 and 67 is effective in silencing gene expression in lentiviral rodent models, BACHD mice, and neural stem cells derived from HD patient embryonic stem cells. Importantly, in cells with glutamine repeats of 44, brain-derived neurotrophic factor (BDNF) axonal trafficking is impaired. When these cells are treated with allele-specific shRNA, BDNF vesicular trafficking improves. Hu and colleagues 9 report on the optimization of single- stranded silencing RNAs (ss-siRNA). The report describes modifying the ss-siRNA length, chemistry, lipid conjugation and structure by introducing mismatches. They found that certain ss-siRNAs with optimized mismatched bases relative to the expanded CAG tract were potent inhibitors of mHTT, both in vivo and in the HdhQ175 knock-in mouse model, as well as silencing a Q47 allele in patient-derived fibroblasts. 1 Beste C, Mückschel M, Elben S, J Hartmann, et al. Behavioral and neurophysiological evidence for the enhancement of cognitive control under dorsal pallidal deep brain stimulation in Huntington's disease. Brain Struct Funct. 2014 May 31. [Epub ahead of print] PubMed ID: 24878825. 2 Cicchetti F, Lacroix S, Cisbani G, Vallières N, et al. Mutant huntingtin is present in neuronal grafts in huntington disease patients. Ann Neurol. 2014 May 6. doi: 10.1002/ana.24174. [Epub ahead of print]. 3 Paulsen JS, Long JD, Johnson HJ, Aylward EA, et al. Clinical and biomarker changes in premanifest Huntington disease show trial feasibility: A decade of the PREDICT-HD study. Front Aging Neurosci. 2014;6:78. Prepublished online Mar 13, 2014. doi: 10.3389/ fnagi.2014.00078.0081528. 7 Wang N, Gray M, Lu X-H, Cantle JP, et al. Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease. Nat Med. 2014 28 Apr; 20:536-541. 8 Drouet V, Ruiz M, Zala D, Feveux M, et al. Allele-specific silencing of mutant huntingtin in rodent brain and human stem cells. PLoS One. 2014 Jun 13;9(6):e99341. doi: 10.1371/ journal.pone.0099341. eCollection 2014. 9 Hu J, Liu J, Yu D, Aiba Y, et al. Exploring the effect of sequence length and composition on allele-selective inhibition of human huntingtin expression by single-stranded silencing RNAs. Nucleic Acid Ther. 2014 Jun;24(3):199-209. doi: 10.1089/nat. 2013.0476. Epub 2014 Apr 2 4 Smith GA, Rocha EM, McLean JR, Hayes MA, et al. Progressive axonal transport and synaptic protein changes correlate with behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse model of Huntington's disease. Hum Mol Genet. 2014 Apr 30. [Epub ahead of print]. 5 Marangoni, M. et al. Age-related axonal swellings precede other neuropathological hallmarks in a knock-in mouse model of Huntington's disease. Neurobiol Aging. 2014 Oct;35(10):2382-2393. doi:10.1016/j.neurobiolaging.2014.04.024. 6 Wong YC, Holzbaur EL. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J Neurosci. 2014 Jan 22;34(4):1293-305. doi: 10.1523/JNEUROSCI. 1870-13.2014. Copyright © Huntington Study Group 2014. All rights reserved. H D I N S I G H T S HD Insights, Vol. 8 3