Journal of Huntington's Disease - Volume 3, issue 1

Authors: Wexler, Alice

Article Type: Other

DOI: 10.3233/JHD-149002

Citation: Journal of Huntington's Disease, vol. 3, no. 1, pp. 1-4, 2014

Authors: Plecash, Alyson R. | Leavitt, Blair R.

Article Type: Review Article

Abstract: Aquatherapy is used for rehabilitation and exercise; water provides a challenging, yet safe exercise environment for many special populations. We have reviewed the use of aquatherapy programs in four neurodegenerative disorders: Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. Results support the use of aquatherapy in Parkinson's disease and multiple sclerosis, however further evidence is required to make specific recommendations in all of the aforementioned disorders.

Keywords: Chorea, Huntington('s) disease, Huntington, Huntington chorea, Parkinson('s) disease, Parkinson, Multiple sclerosis, Amyotrophic lateral sclerosis, Lou Gehrig's disease, hydrotherapy, aquatherapy, aquatic therapy, pool therapy

DOI: 10.3233/JHD-140010

Citation: Journal of Huntington's Disease, vol. 3, no. 1, pp. 5-11, 2014

Authors: Magnusson-Lind, Anna | Davidsson, Marcus | Silajdžić, Edina | Hansen, Christian | McCourt, Andrew C. | Tabrizi, Sarah J. | Björkqvist, Maria

Article Type: Research Article

Abstract: Background: In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology, including progressive skeletal muscle wasting, and common skeletal muscle gene expression changes have been shown in HD mice and human HD. Objective: To highlight possible mechanisms underlying muscle wasting in HD, we examined gene expression in pathways governing skeletal muscle contractility, skeletal myogenesis, skeletal muscle wasting, apoptosis and the NFκB signaling pathway in two HD mouse models (the transgenic R6/2 and full-length knock-in Q175). In addition, we assessed circulating markers that increase in response to skeletal muscle injury, skeletal Troponin I (sTnI), fatty acid binding …protein 3 (FABP3), and Myosin light chain 3 (Myl3). Methods: We measured gene expression in muscle tissue as well as in cultured primary myocytes using qPCR. Concentrations of cytokines and muscle proteins were obtained using multiplex ELISA. Results: Circulating markers of muscle injury (sTnI, FABP3, and Myl3) were significantly increased in mouse serum. In skeletal muscle, we observed reduced gene expression of components involved in muscle contractility, with pronounced downregulation of Acta1, Myh2 and Tnni2, among others. Alongside, we found increased expression of caspases (3 and 8) and key elements of the NFκB signaling pathway, p65/RelA, Tradd, and TRAF5. We also found similar gene expression alterations in cultured primary myocytes from R6/2 mice stimulated with TNF-α. Conclusions: Our results indicate that activation of apoptotic and NFκB pathways occur alongside down-regulation of key compartments of the muscle contractility unit in skeletal muscle of HD mice, and muscle atrophy could possibly be a source of circulating disease progression markers. Show more

Keywords: Muscle atrophy, gene expression, NFκB pathway, Acta1, Troponin, myosin, p65/RelA, Traf5, Tradd

DOI: 10.3233/JHD-130075

Citation: Journal of Huntington's Disease, vol. 3, no. 1, pp. 13-24, 2014

Authors: Buonincontri, Guido | Wood, Nigel I. | Puttick, Simon G. | Ward, Alex O. | Carpenter, T. Adrian | Sawiak, Stephen J. | Morton, A. Jennifer

Article Type: Research Article

Abstract: Background: Increasingly, evidence from studies in both animal models and patients suggests that cardiovascular dysfunction is important in HD. Previous studies measuring function of the left ventricle (LV) in the R6/2 mouse model have found a clear cardiac abnormality, albeit with preserved LV systolic function. It was hypothesized that an impairment of RV function might play a role in this condition via mechanisms of ventricular interdependence. Objective: To investigate RV function in the R6/2 mouse model of Huntington's disease (HD). Methods: Cardiac cine-magnetic resonance imaging (MRI) was used to determine functional parameters in R6/2 mice. In a first experiment, these …parameters were derived longitudinally to determine deterioration of cardiac function with disease progression. A second experiment compared the response to a stress test (using dobutamine) of wildtype and early-symptomatic R6/2 mice. Results: There was progressive deterioration of RV systolic function with age in R6/2 mice. Furthermore, beta-adrenergic stimulation with dobutamine revealed RV dysfunction in R6/2 mice before any overt symptoms of the disease were apparent. Conclusions: This work adds to accumulating evidence of cardiovascular dysfunction in R6/2 mice, describing for the first time the involvement of the right ventricle. Cardiovascular dysfunction should be considered, both when treatment strategies are being designed, and when searching for biomarkers for HD. Show more

Keywords: MRI, right ventricle, cognitive function, heart failure, Huntington's Disease

DOI: 10.3233/JHD-130083

Citation: Journal of Huntington's Disease, vol. 3, no. 1, pp. 25-32, 2014

Authors: Ness, Vanessa | Bestgen, Anne-Kathrin | Saft, Carsten | Beste, Christian

Article Type: Research Article

Abstract: Background: It is well-known that Huntington's disease (HD) affects saccadic processing. However, saccadic dysfunctions in HD may be seen as a result of dysfunctional processes occurring at the oculomotor level prior to the execution of saccades, i.e., at a pre-saccadic level. Virtually nothing is known about possible changes in pre-saccadic processes in HD. Objective: This study examines pre-saccadic processing in pre-manifest HD gene mutation carriers (pre-HDs) by using clinically available EEG measures. Methods: Error rates, pre-saccadic EEG potentials and saccade onset EEG potentials were measured in 14 pre-HDs and case-matched controls performing prosaccades and antisaccades in a longitudinal study over …a 15-month period. Results: The results show that pre-saccadic potentials were changed in pre-HDs, relative to controls and also revealed changes across the 15-month longitudinal period. In particular, pre-saccadic ERP in pre-HDs were characterized by lower amplitudes and longer latencies, which revealed longitudinal changes. These changes were observed for anti-saccades, but not for pro-saccades. Overt saccadic trajectories (potentials) were not different to those in controls, showing that pre-saccadic processes are sensitive to subtle changes in fronto-striatal networks in pre-HDs. Conclusions: Deficits in pre-saccadic processes prior the execution of an erroneous anti-saccade can be seen as an effect of dysfunctional cognitive control in HD. This may underlie saccadic abnormalities and hence a major phenotype of HD. Pre-saccadic EEG potentials preceding erroneous anti-saccades are sensitive to pre-manifest disease progression in HD. Show more

Keywords: Huntington's disease, cognitive control, oculomotor control, inhibition, saccade, antisaccade, EEG

DOI: 10.3233/JHD-130086

Citation: Journal of Huntington's Disease, vol. 3, no. 1, pp. 33-43, 2014

Authors: Nana, Alissa L. | Kim, Eric H. | Thu, Doris C.V. | Oorschot, Dorothy E. | Tippett, Lynette J. | Hogg, Virginia M. | Synek, Beth J. | Roxburgh, Richard | Waldvogel, Henry J. | Faull, Richard L.M.

Article Type: Research Article

Abstract: Huntington's disease is an autosomal dominant neurodegenerative disease characterized by neuronal degeneration in the basal ganglia and cerebral cortex, and a variable symptom profile. Although progressive striatal degeneration is known to occur and is related to symptom profile, little is known about the cellular basis of symptom heterogeneity across the entire cerebral cortex. To investigate this, we have undertaken a double blind study using unbiased stereological cell counting techniques to determine the pattern of cell loss in six representative cortical regions from the frontal, parietal, temporal, and occipital lobes in the brains of 14 Huntington's disease cases and 15 controls. …The results clearly demonstrate a widespread loss of total neurons and pyramidal cells across all cortical regions studied, except for the primary visual cortex. Importantly, the results show that cell loss is remarkably variable both within and between Huntington's disease cases. The results also show that neuronal loss in the primary sensory and secondary visual cortices relate to Huntington's disease motor symptom profiles, and neuronal loss across the associational cortices in the frontal, parietal and temporal lobes is related to both Huntington's disease motor and to mood symptom profiles. This finding considerably extends a previous study (Thu et al., Brain, 2010; 133:1094–1110) which showed that neuronal loss in the primary motor cortex was related specifically to the motor symptom profiles while neuronal loss in the anterior cingulate cortex was related specifically to mood symptom profiles. The extent of cortical cell loss in the current study was generally related to the striatal neuropathological grade, but not to CAG repeat length on the HTT gene. Overall our findings show that Huntington's disease is characterized by a heterogeneous pattern of neuronal cell loss across the entire cerebrum which varies with symptom profile. Show more

Keywords: Huntington disease, cerebral cortex, pathology, clinical, neuroanatomy

DOI: 10.3233/JHD-140092

Citation: Journal of Huntington's Disease, vol. 3, no. 1, pp. 45-64, 2014

Authors: Lee, John H. | Sowada, Matthew J. | Boudreau, Ryan L. | Aerts, Andrea M. | Thedens, Daniel R. | Nopoulos, Peg | Davidson, Beverly L.

Article Type: Research Article

Abstract: In Huntington's disease (HD) mutant HTT is ubiquitously expressed yet the striatum undergoes profound early degeneration. Cell culture studies suggest that a striatal-enriched protein, Rhes, may account for this vulnerability. We investigated the therapeutic potential of silencing Rhes in vivo using inhibitory RNAs (miRhes). While Rhes suppression was tolerated in wildtype mice, it failed to improve rotarod function in two distinct HD mouse models. Additionally, miRhes treated HD mice had increased anxiety-like behaviors and enhanced striatal atrophy as measured by longitudinal MRI when compared to control treated mice. These findings raise caution regarding the long-term implementation of inhibiting Rhes as …a therapy for HD. Show more

Keywords: Huntington disease, Rhes, rasd2, neurodegenerative disease, genetic therapies, RNA interference

DOI: 10.3233/JHD-140094

Citation: Journal of Huntington's Disease, vol. 3, no. 1, pp. 65-71, 2014

Authors: Tebbenkamp, Andrew T.N. | Xu, Guilian | Siemienski, Zoe B. | Janus, Christopher | Fromholt, Susan E. | Brown, Hilda H. | Swing, Debbie | Tessarollo, Lino | Borchelt, David R.

Article Type: Research Article

Abstract: Background: N-terminal cleavage products of mutant huntingtin (htt) generate pathologic neuronal inclusion bodies. The precise length of the htt fragment, termed Cp-A/1, that produces HD pathologic inclusions is unknown. Objective: We sought to elucidate the protein sequence elements within the N-terminus of htt that mediate its proteolysis based on a model in which engineered htt fragments terminating at residue 171 are cleaved to produce Cp-A/1 fragments. Methods: We expressed htt N171 cDNAs harboring a series of experimental mutations in the presumptive cleavage site that generates Cp-A/1 in cells to identify cleavage resistant mutants of htt N171. One of these constructs …was expressed in mice, followed by analysis using immunoblots of brain extracts and immunohistochemistry of transgenic mouse brain tissues. Results: Using the HEK293 cell model, mutagenesis studies mapped the cleavage site in htt N171 to sequences between residues 105–114. Mutation of 8 positively charged residues (H, K, R) located between residues 88 and 114 to alanine to neutralize the charge also blocked the generation of Cp-A/1 like fragments. Transgenic mice expressing this latter construct, termed N171-82Q-N8, developed phenotypes similar to previously characterized N171-82Q transgenic mice, including rotarod deficiency, intranuclear inclusions, and premature death. Surprisingly, the N171-82Q-N8 protein was efficiently cleaved in vivo to produce Cp-A/1 fragments that accumulated as insoluble inclusions. Conclusion: Mutagenesis of htt to identify critical amino acids that direct its cleavage predicted a role for charged residues in the sequence flanking the presumptive cleavage site. However, the role for these residues could not be confirmed in vivo. The basis for the discrepancy between predicted outcomes in HEK293 cells and the mouse models remain unresolved, but the data provide another validation of the hypothesis that Cp-A/1 fragments of mutant htt can induce HD-like phenotypes. Show more

Keywords: Huntington's disease, protein processing, mutagenesis, transgenic mice, protease, intranuclear inclusion bodies

DOI: 10.3233/JHD-130087

Citation: Journal of Huntington's Disease, vol. 3, no. 1, pp. 73-86, 2014

Article Type: Other

DOI: 10.3233/JHD-149003

Citation: Journal of Huntington's Disease, vol. 3, no. 1, pp. 87-87, 2014