Journal of Huntington's Disease - Volume 2, issue 1

Authors: Leavitt, Blair R. | Thompson, Leslie M.

Article Type: Other

DOI: 10.3233/JHD-130003

Citation: Journal of Huntington's Disease, vol. 2, no. 1, pp. 1-1, 2013

Authors: Morton, A. Jennifer | Howland, David S.

Article Type: Review Article

Abstract: The dominant nature of the Huntington's disease gene mutation has allowed genetic models to be developed in multiple species, with the mutation causing an abnormal neurological phenotype in all animals in which it is expressed. Many different rodent models have been generated. The most widely used of these, the transgenic R6/2 mouse, carries the mutation in a fragment of the human huntingtin gene and has a rapidly progressive and fatal neurological phenotype with many relevant pathological changes. Nevertheless, their rapid decline has been frequently questioned in the context of a disease that takes years to manifest in humans, and strenuous …efforts have been made to make rodent models that are genetically more ‘relevant’ to the human condition, including full length huntingtin gene transgenic and knock-in mice. While there is no doubt that we have learned, and continue to learn much from rodent models, their usefulness is limited by two species constraints. First, the brains of rodents differ significantly from humans in both their small size and their neuroanatomical organization. Second, rodents have much shorter lifespans than humans. Here, we review new approaches taken to these challenges in the development of models of Huntington's disease in large brained, long-lived animals. We discuss the need for such models, and how they might be used to fill specific niches in preclinical Huntington's disease research, particularly in testing gene-based therapeutics. We discuss the advantages and disadvantages of animals in which the prodromal period of disease extends over a long time span. We suggest that there is considerable ‘value added’ for large animal models in preclinical Huntington's disease research. Show more

Keywords: CAG repeat, polyglutamine, sheep, non-human primate, monkey, minipig, neurodegeneration, sleep, circadian

DOI: 10.3233/JHD-130050

Citation: Journal of Huntington's Disease, vol. 2, no. 1, pp. 3-19, 2013

Authors: Rees, Elin M. | Scahill, Rachael I. | Hobbs, Nicola Z.

Article Type: Review Article

Abstract: Identifying markers able to characterise the progression of Huntington's Disease (HD) is of great importance to the HD research community, as such markers may provide valuable outcome measures in future clinical trials. Neuroimaging measures are obvious candidates because of their clear relevance to the neuropathology of the disease. Many also show improved precision and sensitivity compared with standard functional scales. This review summarizes findings from the wealth of longitudinal imaging studies in the literature, focusing on the most widely available imaging modalities: structural MRI (volumetric and diffusion imaging), functional MRI and PET. We discuss the longitudinal sensitivity, reproducibility and feasibility …of each imaging modality for use in clinical trials. Show more

Keywords: Huntington's disease, longitudinal studies, biomarkers, magnetic resonance imaging, diffusion mri, functional mri, positron emission tomography

DOI: 10.3233/JHD-120030

Citation: Journal of Huntington's Disease, vol. 2, no. 1, pp. 21-39, 2013

Authors: van der Bom, I.M.J. | Moser, R.P. | Gao, G. | Mondo, E. | O'Connell, D. | Gounis, M.J. | McGowan, S. | Chaurette, J. | Bishop, N. | Sena-Esteves, M.S. | Mueller, C. | Aronin, N.

Article Type: Short Communication

Abstract: Our goal is delivery of a long-term treatment for Huntington's disease. We administer intracerebrally in sheep adeno-associated virus (AAV) to establish optimal safety, spread and neuronal uptake of AAV based therapeutics. Sheep have large gyrencephalic brains and offer the opportunity to study a transgenic Huntington's disease model. However, lack of a relevant brain stereotactic atlas and the difficulty of skull fixation make conventional stereotaxy unreliable. We describe a multi-modal image-guidance technique to achieve accurate placement of therapeutics into the sheep striatum.

Keywords: Sheep brain, stereotaxis placement, huntingtin therapeutics

DOI: 10.3233/JHD-130053

Citation: Journal of Huntington's Disease, vol. 2, no. 1, pp. 41-45, 2013

Authors: Baxa, Monika | Hruska-Plochan, Marian | Juhas, Stefan | Vodicka, Petr | Pavlok, Antonin | Juhasova, Jana | Miyanohara, Atsushi | Nejime, Tetsuya | Klima, Jiri | Macakova, Monika | Marsala, Silvia | Weiss, Andreas | Kubickova, Svatava | Musilova, Petra | Vrtel, Radek | Sontag, Emily M. | Thompson, Leslie M. | Schier, Jan | Hansikova, Hana | Howland, David S. | Cattaneo, Elena | DiFiglia, Marian | Marsala, Martin | Motlik, Jan

Article Type: Research Article

Abstract: Background: Some promising treatments for Huntington's disease (HD) may require pre-clinical testing in large animals. Minipig is a suitable species because of its large gyrencephalic brain and long lifespan. Objective: To generate HD transgenic (TgHD) minipigs encoding huntingtin (HTT)1–548 under the control of human HTT promoter. Methods: Transgenesis was achieved by lentiviral infection of porcine embryos. PCR assessment of gene transfer, observations of behavior, and postmortem biochemical and immunohistochemical studies were conducted. Results: One copy of the human HTT transgene encoding 124 glutamines integrated into chromosome 1 q24-q25 and successful germ line transmission occurred through successive generations (F0, F1, F2 …and F3 generations). No developmental or gross motor deficits were noted up to 40 months of age. Mutant HTT mRNA and protein fragment were detected in brain and peripheral tissues. No aggregate formation in brain up to 16 months was seen by AGERA and filter retardation or by immunostaining. DARPP32 labeling in WT and TgHD minipig neostriatum was patchy. Analysis of 16 month old sibling pairs showed reduced intensity of DARPP32 immunoreactivity in neostriatal TgHD neurons compared to those of WT. Compared to WT, TgHD boars by one year had reduced fertility and fewer spermatozoa per ejaculate. In vitro analysis revealed a significant decline in the number of WT minipig oocytes penetrated by TgHD spermatozoa. Conclusions: The findings demonstrate successful establishment of a transgenic model of HD in minipig that should be valuable for testing long term safety of HD therapeutics. The emergence of HD-like phenotypes in the TgHD minipigs will require more study. Show more

Keywords: Huntington's disease, mutant huntingtin, minipigs, large animal model, lentiviral transgenesis, FISH analysis, mRNA and protein expression, immunohistochemistry, DARPP32, AGERA assay, TR-FRET assay, spermatozoa

DOI: 10.3233/JHD-130001

Citation: Journal of Huntington's Disease, vol. 2, no. 1, pp. 47-68, 2013

Authors: Zhang, Hongyu | Petit, Géraldine H. | Gaughwin, Philip M. | Hansen, Christian | Ranganathan, Srikanth | Zuo, Xiaoyi | Smith, Ruben | Roybon, Laurent | Brundin, Patrik | Mobley, William C. | Li, Jia-Yi

Article Type: Research Article

Abstract: Background: Recent studies in Huntington's disease (HD) mouse models and patients suggest that hippocampal neurons and their cholinergic afferents are involved in the cognitive deficits seen in the disease. Nerve growth factor (NGF) is an essential regulator of cholinergic neuronal survival and neurotransmission. Objective: We asked whether NGF might be involved in HD and if intra-cerebroventricular infusion of NGF can rescue hippocampal cholinergic neuronal markers, restore neurogenesis, and improve the spatial working memory in R6/1 mouse model of HD. Methods: We quantified NGF protein level by enzyme-linked immunosorbent assay (ELISA), intracerebroventricularly infused NGF, assessed cholinergic neuronal markers by Western blotting …and quantitative RT-PCR, evaluated neurogenesis by immunohistochemistry, and studied spatial working memory using radial maze. Results: By quantifying NGF protein in the hippocampus of the R6/1 mice at different ages, we found progressive decreases in NGF protein levels. We then increased NGF levels in the R6/1 mice through intra-cerebroventricular infusion. We observed elevations of the cholinergic neurochemical markers vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) in the hippocampus and in the septal region, which contain the cell bodies of basal forebrain cholinergic neurons (BFCNs), but not in the striatum that harbors cholinergic interneurons. Finally, we found that NGF infusion also restored hippocampal neurogenesis and improved spatial working memory. Conclusions: Our results suggest that intracerebral injections of NGF might be a valuable therapy against cognitive symptoms in HD and should be further studied in HD animal models and patients. Show more

Keywords: Nerve growth factor, cholinergic function, neurogenesis, huntington's disease, R6/1 mice

DOI: 10.3233/JHD-120026

Citation: Journal of Huntington's Disease, vol. 2, no. 1, pp. 69-82, 2013

Authors: Shin, Chae Won | Choi, Yoon Jae | Kim, Manho | Jeon, Beom Seok

Article Type: Research Article

Abstract: Background: There have been epidemiological studies of Huntington's disease (HD) in various populations and nations. Only a few studies describing clinical characteristics have been reported in Asia. Objective: To conduct preliminary analyses of demographic, clinical and genetic characteristics of HD in South Korea. Methods: From 1994 to 2011, thirty six subjects were diagnosed as HD in Seoul National University Hospital. Demographic, clinical and genetic data were carefully analyzed in all subjects. Results: Mean age of onset was 46.5 ± 12.7 years and mean expanded CAG repeat size was 45.4 ± 4.7. Twenty-eight subjects (80%) had a family history of HD. …Chorea was the most frequent symptom at first visit (89%). Proportion of cognitive decline (36%) and psychiatric symptom (28%) at first visit were lower than proportion of previous reports. A negative correlation (Pearson correlation coefficient −0.757, p = 0.001) was found between expanded CAG repeat size and age of onset. Seven subjects without family history of HD had higher mean age of onset (54.0 ± 8.1) and smaller expanded CAG repeat size (42.4 ± 2.7). Cognitive problems at first visit of subjects without family history were more prominent than those with family history (86% vs. 25%). Conclusions: This study is the first demographic, clinical and genetic analyses in South Korea. These results will be helpful to stimulate more large-scale research in South Korea and other Asian nations. Show more

Keywords: Huntington disease, chorea, trinucleotide repeat expansion, demographics, genetics

DOI: 10.3233/JHD-120040

Citation: Journal of Huntington's Disease, vol. 2, no. 1, pp. 83-87, 2013

Authors: Schönberger, Sarah J. | Jezdic, Dina | Faull, Richard L.M. | Cooper, Garth J.S.

Article Type: Research Article

Abstract: Background: Huntington's disease (HD) is a neurodegenerative disorder in which the aetiological defect is inherited or spontaneous mutation in the HTT gene, which alters the structure of the corresponding huntingtin protein and initiates a pathogenetic cascade that ultimately leads to or causes dementia. Objective: Here our main objective was to elucidate further the pathogenic processes that underlie neurodegeneration in HD. Methods: By using two-dimensional gel electrophoresis we performed a proteomic case-control study of two brain regions in post-mortem human tissue from seven well-characterized HD patients and eight matched controls. Results: In the middle frontal gyrus we identified twenty-two differentially-expressed proteins …whereas by contrast in visual cortex only seven were altered. Twenty of these proteins have not to our knowledge been associated with the pathogenesis of HD before although all functional families implicated have previously been linked to other neurodegenerative diseases. Most of the proteins identified play roles in cell stress responses, apoptosis, metabolic regulation linked to type-2 diabetes, the ubiquitin-proteasome system, or protein trafficking/endocytosis. Conclusions: We propose that HTT mutations lead to or cause functional impairment of these pathways and that simultaneous restoration of their functions by targeted pharmacotherapy could ameliorate the signs and symptoms of HD. These studies provide a unique illustration of the interlinked disease processes that underpin/contribute to the pathogenesis of neurodegeneration in a genetically-mediated disorder of protein structure, and provide a signpost towards the design of new therapeutic interventions. Show more

Keywords: Dementia, human brain, oxidative stress, metabolic stress, type-2 diabetes, copper, experimental therapeutics

DOI: 10.3233/JHD-120044

Citation: Journal of Huntington's Disease, vol. 2, no. 1, pp. 89-99, 2013

Authors: Xiang, Zhongmin | Krainc, Dimitri

Article Type: Research Article

Abstract: The coactivator PGC1α plays a role in the transcriptional regulation of energy metabolism and its deficiency has been implicated in abnormalities of myelination and oligodendrocyte differentiation in Huntington's disease (HD). In an effort to activate PGC1α in oligodendrocytes, we found that overexpression of SIRT1 or treatment with resveratrol (RSV) and SRT1720 upregulated PGC1α expression and increased oligodendrocyte differentiation. Interestingly, in oligodendrocytes expressing mutant huntingtin, SRT1720 but not RSV was able to restore PGC1α expression and the differentiation. These results suggest that pharmacological activation of PGC1α in oligodendrocytes by SRT1720 may provide a therapeutic opportunity for correction of deficient myelination in …HD. Show more

Keywords: Oligodendrocyte, PGC1α, SIRT1, resveratrol, differentiation, Huntington's disease

DOI: 10.3233/JHD-130046

Citation: Journal of Huntington's Disease, vol. 2, no. 1, pp. 101-105, 2013

Authors: Vittori, Angelica | Orth, Michael | Roos, Raymund A. C. | Outeiro, Tiago F. | Giorgini, Flaviano | Hollox, Edward J. | REGISTRY investigators of the European Huntington's Disease Network

Article Type: Research Article

Abstract: Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a CAG triplet repeat tract in the huntingtin gene. While the length of this CAG expansion is the major determinant of the age of onset (AO), other genetic factors have also been shown to play a modulatory role. Recent evidence suggests that neuroinflammation is a pivotal factor in the pathogenesis of HD, and that targeting this process may have important therapeutic ramifications. The human β-defensin 2 (hBD2) – encoded by DEFB4 – is an antimicrobial peptide that exhibits inducible expression in astrocytes during inflammation …and is an important regulator of innate and adaptive immune response. Therefore, DEFB4 may contribute to the neuroinflammatory processes observed in HD. Objective: In this study we tested the hypothesis that copy number variation (CNV) of the β-defensin region, including DEFB4, modifies the AO in HD. Methods and results: We genotyped β-defensin CNV in 490 HD individuals using the paralogue ratio test and found no association between β-defensin CNV and onset of HD. Conclusions: We conclude that it is unlikely that DEFB4 plays a role in HD pathogenesis. Show more

Keywords: Genetic modifier, copy number variation, inflammation

DOI: 10.3233/JHD-130047

Citation: Journal of Huntington's Disease, vol. 2, no. 1, pp. 107-124, 2013