Journal of Huntington's Disease - Volume 2, issue 4

Authors: Marques Sousa, Cristovao | Humbert, Sandrine

Article Type: Review Article

Abstract: Huntingtin is the protein mutated in Huntington disease, a dominant inherited neurodegenerative disorder. Huntingtin is ubiquitously expressed throughout the body, however its role outside the central nervous system has been overlooked. This review focuses on the peripheral distribution of huntingtin. It also highlights that huntingtin has central cellular functions, the importance of which may extend beyond the nervous system. Because of the breadth of huntingtin expression and functions, mutant huntingtin undoubtedly causes peripheral disturbances and may be involved in other non neuronal pathologies.

Keywords: Huntingtin, peripheral tissues, expression pattern, huntingtin function

DOI: 10.3233/JHD-130082

Citation: Journal of Huntington's Disease, vol. 2, no. 4, pp. 395-403, 2013

Authors: Crook, Zachary R. | Housman, David E.

Article Type: Review Article

Abstract: Though 20 years have now passed since the cloning of the huntingtin gene (HTT), there remains no treatment for Huntington's Disease (HD) that alters the course of disease or lifespan of patients. The reasons for this are manifold, and likely have to do with the diverse cellular pathways disrupted by mutant HTT (mHTT) protein expression. Furthermore, the evaluation of efficacy using a putative intervention is complex, largely due to the slow course of disease and variability in the classic techniques for evaluating patient symptoms and quality of life, which make the patient populations and duration of trials particularly imposing. However, …there are signs for hope both in the clinic and at the bench. This review serves three purposes. It discusses the known cellular pathologies in HD, the current and upcoming methods for clinical evaluation of disease progress, and the tested and untested interventions proposed to counter the progression in animal models and patients. With the vast knowledge of pathology accumulated over two decades of modeling HD in animals and following it in patients, as well as the advances in intervention techniques both pharmaceutical and genetic, there is reason for optimism in the field. Such optimism can only be tempered by the lack of success in the clinic to this point, though patients, scientists, and clinicians all remain enthusiastic about each new trial, and progress can only continue until an effective treatment is found. Show more

Keywords: Neurodegeneration, Huntington's Disease, disease mechanisms, therapeutics, aggregation, chaperones, excitotoxicity, gene therapy

DOI: 10.3233/JHD-130072

Citation: Journal of Huntington's Disease, vol. 2, no. 4, pp. 405-436, 2013

Authors: Crook, Zachary R. | Housman, David E.

Article Type: Short Communication

Abstract: Rapidly identifying targets for Huntington's Disease (HD) therapeutics in relevant mouse models could hasten the development of patient interventions. We have recently described a method for rapidly and quantitatively measuring the progression of HD-like symptoms in mouse models. Because this method uses flow cytometry to measure GFP levels in affected neurons, it is amenable to pooled approaches. Here we describe a continuation of this work, using pools of shRNA-delivering AAV vectors and high throughput sequencing to determine which hairpins in a mixed population are most effective at preventing the transcriptional dysregulation phenotype of R6/2 mice.

Keywords: Neurodegeneration, Huntington's Disease, viral vectors, pooled screening, neuroprotection, gene expression

DOI: 10.3233/JHD-130073

Citation: Journal of Huntington's Disease, vol. 2, no. 4, pp. 437-441, 2013

Authors: Wang, Nan | Lu, Xiao-Hong | Sandoval, Susana V. | Yang, X. William

Article Type: Short Communication

Abstract: Background: C2-8 is a small molecule inhibitor of polyglutamine aggregation and can reduce photoreceptor neurodegeneration in a Drosophila model of Huntington's disease (HD). Further preclinical studies have shown that oral administration of C2-8 in R6/2 HD transgenic mice can penetrate into the brain, reduce mHTT-exon1 aggregation, improve motor performance and diminish striatal neuron atrophy. Objective: In this independent preclinical study, we aimed to evaluate the pharmacokinetic properties and therapeutic efficacy of C2-8 intraperitoneal (IP) delivery in the R6/2 HD mouse. Methods: R6/2 mice were IP injected with low dose C2-8 (10 mg/kg), high dose C2-8 (20 mg/kg), or vehicle twice …daily from 3 weeks to 3 months old. Longitudinal behavioral tests (accelerating Rotarod and wire-hang) were performed to evaluate the motor deficits, and neuropathology was measured by unbiased stereology. Results: We confirmed that the compound has good blood-brain-barrier penetration after acute or sub-chronic intraperitoneal delivery. Chronic treatment with C2-8 in R6/2 mice results in a significant reduction of nuclear mHTT aggregate volume in the brains, replicating a key finding of C2-8 as a polyglutamine aggregation inhibitor in vivo. However, by comparing HD mice with C2-8 treatment to those with vehicle treatment, we were unable to demonstrate significant amelioration of motor deficits using Rotarod and wire-hang tests. Moreover, we did not observe improvement in the striatal neurodegenerative pathology, as measured by brain weight, striatal volume, and striatal neuron volume in the C2-8 treated R6/2 mice. Conclusions: Our study supports the practice of independent preclinical studies for novel molecules in HD therapeutic development and suggests that the use of alternative delivery strategies and full-length HD mouse models are likely needed to further assess whether the aggregate-inhibiting properties of C2-8 can be consistently translated into a preclinical benefit in HD mice. Show more

Keywords: Huntington's disease, huntingtin, preclinical, aggregate, R6/2, C2-8

DOI: 10.3233/JHD-130074

Citation: Journal of Huntington's Disease, vol. 2, no. 4, pp. 443-451, 2013

Authors: Aubeeluck, A. | Buchanan, H. | Stupple, E.

Article Type: Other

DOI: 10.3233/JHD-139008

Citation: Journal of Huntington's Disease, vol. 2, no. 4, pp. 453-454, 2013

Authors: Hagell, Peter | Smith, Steve

Article Type: Other

DOI: 10.3233/JHD-139009

Citation: Journal of Huntington's Disease, vol. 2, no. 4, pp. 455-457, 2013

Authors: Valencia, Antonio | Sapp, Ellen | Kimm, Jeffrey S. | McClory, Hollis | Ansong, Kwadwo A. | Yohrling, George | Kwak, Seung | Kegel, Kimberly B. | Green, Karin M. | Shaffer, Scott A. | Aronin, Neil | DiFiglia, Marian

Article Type: Research Article

Abstract: Background: Synaptic connections are disrupted in patients with Huntington's disease (HD). Synaptosomes from postmortem brain are ideal for synaptic function studies because they are enriched in pre- and post-synaptic proteins important in vesicle fusion, vesicle release, and neurotransmitter receptor activation. Objective: To examine striatal synaptosomes from 3, 6 and 12 month old WT and Hdh140Q/140Q knock-in mice for levels of synaptic proteins, methionine oxidation, and glutamate release. Methods: We used Western blot analysis, glutamate release assays, and liquid chromatography tandem mass spectrometry (LC-MS/MS). Results: Striatal synaptosomes of 6 month old Hdh140Q/140Q mice had less DARPP32, syntaxin 1 and …calmodulin compared to WT. Striatal synaptosomes of 12 month old Hdh140Q/140Q mice had lower levels of DARPP32, alpha actinin, HAP40, Na+ /K+ -ATPase, PSD95, SNAP-25, TrkA and VAMP1, VGlut1 and VGlut2, increased levels of VAMP2, and modifications in actin and calmodulin compared to WT. More glutamate released from vesicles of depolarized striatal synaptosomes of 6 month old Hdh140Q/140Q than from age matched WT mice but there was no difference in glutamate release in synaptosomes of 3 and 12 month old WT and Hdh140Q/140Q mice. LC-MS/MS of 6 month old Hdh140Q/140Q mice striatal synaptosomes revealed that about 4% of total proteins detected (>600 detected) had novel sites of methionine oxidation including proteins involved with vesicle fusion, trafficking, and neurotransmitter function (synaptophysin, synapsin 2, syntaxin 1, calmodulin, cytoplasmic actin 2, neurofilament, and tubulin). Altered protein levels and novel methionine oxidations were also seen in cortical synaptosomes of 12 month old Hdh140Q/140Q mice. Conclusions: Findings provide support for early synaptic dysfunction in Hdh140Q/140Q knock-in mice arising from altered protein levels, oxidative damage, and impaired glutamate neurotransmission and suggest that study of synaptosomes could be of value for evaluating HD therapies. Show more

Keywords: Mutant huntingtin, HD, synaptosomes, oxidative damage, methionine oxidation, glutamate release, synaptic proteins, mass spectrometry

DOI: 10.3233/JHD-130080

Citation: Journal of Huntington's Disease, vol. 2, no. 4, pp. 459-475, 2013

Authors: Aylward, Elizabeth H. | Harrington, Deborah L. | Mills, James A. | Nopoulos, Peggy C. | Ross, Christopher A. | Long, Jeffrey D. | Liu, Dawei | Westervelt, Holly K. | Paulsen, Jane S. | the PREDICT-HD Investigators and Coordinators of the Huntington Study Group

Article Type: Research Article

Abstract: Background: Neuroimaging studies suggest that volumetric MRI measures of specific brain structures may serve as excellent biomarkers in future clinical trials of Huntington disease (HD). Objective: Demonstration of the clinical significance of these measures is an important step in determining their appropriateness as potential outcome measures. Methods: Measures of gray- and white-matter lobular volumes and subcortical volumes (caudate, putamen, globus pallidus, thalamus, nucleus accumbens, hippocampus) were obtained from MRI scans of 516 individuals who tested positive for the HD gene expansion, but were not yet exhibiting signs or symptoms severe enough to warrant diagnosis (“pre-HD”). MRI volumes (corrected for intracranial …volume) were correlated with cognitive, motor, psychiatric, and functional measures known to be sensitive to subtle changes in pre-HD. Results: Caudate, putamen, and globus pallidus volumes consistently correlated with cognitive and motor, but not psychiatric or functional measures in pre-HD. Volumes of white matter, nucleus accumbens, and thalamus, but not cortical gray matter, also correlated with some of the motor and cognitive measures. Conclusions: Results of regression analyses suggest that volumes of basal ganglia structures contributed more highly to the prediction of most motor and cognitive variables than volumes of other brain regions. These results support the use of volumetric measures, especially of the basal ganglia, as outcome measures in future clinical trials in pre-HD. Results may also assist investigators in selecting the most appropriate measures for treatment trials that target specific clinical features or regions of neuropathology. Show more

Keywords: Huntington disease, magnetic resonance imaging, cognitive, psychiatric, motor

DOI: 10.3233/JHD-130076

Citation: Journal of Huntington's Disease, vol. 2, no. 4, pp. 477-489, 2013

Authors: Liu, Wanzhao | Chaurette, Joanna | Pfister, Edith L. | Kennington, Lori A. | Chase, Kathryn O. | Bullock, Jocelyn | Vonsattel, Jean Paul G. | Faull, Richard L.M. | Macdonald, Douglas | DiFiglia, Marian | Zamore, Phillip D. | Aronin, Neil

Article Type: Research Article

Abstract: Background: Huntington's disease is caused by expansion of CAG trinucleotide repeats in the first exon of the huntingtin gene, which is essential for both development and neurogenesis. Huntington's disease is autosomal dominant. The normal allele contains 6 to 35 CAG triplets (average, 18) and the mutant, disease-causing allele contains >36 CAG triplets (average, 42). Objective: We examined 279 postmortem brain samples, including 148 HD and 131 non-HD controls. A total of 108 samples from 87 HD patients that are heterozygous at SNP rs362307, with a normal allele (18 to 27 CAG repeats) and a mutant allele (39 to 73 CAG …repeats) were used to measure relative abundance of mutant and wild-type huntingtin mRNA. Methods: We used allele-specific, quantitative RT-PCR based on SNP heterozygosity to estimate the relative amount of mutant versus normal huntingtin mRNA in postmortem brain samples from patients with Huntington's disease. Results: In the cortex and striatum, the amount of mRNA from the mutant allele exceeds that from the normal allele in 75% of patients. In the cerebellum, no significant difference between the two alleles was evident. Brain tissues from non-HD controls show no significant difference between two alleles of huntingtin mRNAs. Allelic differences were more pronounced at early neuropathological grades (grades 1 and 2) than at late grades (grades 3 and 4). Conclusion: More mutant HTT than normal could arise from increased transcription of mutant HTT allele, or decreased clearance of mutant HTT mRNA, or both. An implication is that equimolar silencing of both alleles would increase the mutant HTT to normal HTT ratio. Show more

Keywords: Huntington's disease, mRNA, HTT mRNA alleles, Huntington's disease neuropathology grade

DOI: 10.3233/JHD-130079

Citation: Journal of Huntington's Disease, vol. 2, no. 4, pp. 491-500, 2013

Authors: Russo, Cinzia V. | Salvatore, Elena | Saccà, Francesco | Tucci, Tecla | Rinaldi, Carlo | Sorrentino, Pierpaolo | Massarelli, Marco | Rossi, Fabiana | Savastano, Silvia | Di Maio, Luigi | Filla, Alessandro | Colao, Annamaria | De Michele, Giuseppe

Article Type: Research Article

Abstract: Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the HTT gene. There is increasing evidence pointing towards an involvement of the endocrine system in HD. Recent studies, investigating the increased risk of diabetes mellitus and impaired insulin sensitivity and secretion in HD patients, led to contradictory results. Objective: To investigate glucose homeostasis in HD. Methods: Twenty-eight consecutive patients with HD and 28 healthy controls were matched for age, sex, and BMI. Diagnosis of HD was confirmed genetically. Clinical tools for assessment were the Unified Huntington's Disease Rating Scale …(UHDRS) motor section and the Total Function Capacity (TFC). Basal metabolic and endocrine investigations and a 2-hour 75-g oGTT were performed. We used the homeostasis model assessment of insulin resistance (HOMA-IR) as index of insulin sensitivity and the insulinogenic index to assess insulin secretion. Results: HD patients did not differ from the controls with respect to fasting plasma glucose, insulin sensitivity and secretion. CAG expansion size, disease stage and duration, or BMI did not influence HOMA-IR and insulinogenic index. Patients showed lower serum glucose (−19%) and insulin levels (−48%) at 30 min and higher serum insulin levels at 90 (+132%) and 120 min (+380%). Conclusions: Our data do not support an increased risk of diabetes among HD patients although they show glucose regulation abnormalities with a flat glucose curve and delayed insulin peak after oral glucose load. Show more

Keywords: Huntington's disease, insulin sensitivity, insulin secretion, glucose regulation

DOI: 10.3233/JHD-130078

Citation: Journal of Huntington's Disease, vol. 2, no. 4, pp. 501-507, 2013