Journal of Huntington's Disease - Volume 5, issue 2

Authors: Tousley, Adelaide | Kegel-Gleason, Kimberly B.

Article Type: Review Article

Abstract: Induced pluripotent stem cells (iPSCs) derived from controls and patients can act as a starting point for in vitro differentiation into human brain cells for discovery of novel targets and treatments for human disease without the same ethical limitations posed by embryonic stem cells. Numerous groups have successfully produced and characterized Huntington’s disease (HD) iPSCs with different CAG repeat lengths, including cells from patients with one or two HD alleles. HD iPSCs and the neural cell types derived from them recapitulate some disease phenotypes found in both human patients and animal models. Although these discoveries are encouraging, the use …of iPSCs for cutting edge and reproducible research has been limited due to some of the inherent problems with cell lines and the technological differences in the way laboratories use them. The goal of this review is to summarize the current state of the HD iPSC field, and to highlight some of the issues that need to be addressed to maximize their potential as research tools. Show more

Keywords: Huntingtin, Huntington’s disease, HTT, induced neuron, induced pluripotent stem cell, neural stem cell, neurodegenerative disorder

DOI: 10.3233/JHD-160199

Citation: Journal of Huntington's Disease, vol. 5, no. 2, pp. 99-131, 2016

Authors: Billes, Viktor | Kovács, Tibor | Hotzi, Bernadette | Manzéger, Anna | Tagscherer, Kinga | Komlós, Marcell | Tarnóci, Anna | Pádár, Zsolt | Erdős, Attila | Bjelik, Annamaria | Legradi, Adam | Gulya, Károly | Gulyás, Balázs | Vellai, Tibor

Article Type: Research Article

Abstract: Background: Autophagy, a lysosome-mediated self-degradation process of eukaryotic cells, serves as a main route for the elimination of cellular damage [1–3 ]. Such damages include aggregated, oxidized or misfolded proteins whose accumulation can cause various neurodegenerative pathologies, including Huntington’s disease (HD). Objective: Here we examined whether enhanced autophagic activity can alleviate neurophatological features in a Drosophila model of HD (the transgenic animals express a human mutant Huntingtin protein with a long polyglutamine repeat, 128Q). Methods: We have recently identified an autophagy-enhancing small molecule, AUTEN-67 (autophagy enhancer 67), with potent neuroprotective effects [4 ]. AUTEN-67 …was applied to induce autophagic activity in the HD model used in this study. Results: We showed that AUTEN-67 treatment interferes with the progressive accumulation of ubiquitinated proteins in the brain of Drosophila transgenic for the pathological 128Q form of human Huntingtin protein. The compound significantly improved the climbing ability and moderately extended the mean life span of these flies. Furthermore, brain tissue samples from human patients diagnosed for HD displayed increased levels of the autophagy substrate SQSTM1/p62 protein, as compared with controls. Conclusions: These results imply that AUTEN-67 impedes the progression of neurodegenerative symptoms characterizing HD, and that autophagy is a promising therapeutic target for treating this pathology. In humans, AUTEN-67 may have the potential to delay the onset and decrease the severity of HD. Show more

Keywords: Huntington’s disease, Huntingtin, polyQ, neurodegeneration, autophagy, AUTEN-67, Drosophila, climbing assay, ubiquitinated proteins, Ref(2)P/SQSTM1/p62

DOI: 10.3233/JHD-150180

Citation: Journal of Huntington's Disease, vol. 5, no. 2, pp. 133-147, 2016

Authors: Yhnell, Emma | Dunnett, Stephen B. | Brooks, Simon P.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a rare, incurable neurodegenerative disorder caused by a CAG trinucleotide expansion with the first exon of the huntingtin gene. Numerous knock-in mouse models are currently available for modelling HD. However, before their use in scientific research, these models must be characterised to determine their face and predictive validity as models of the disease and their reliability in recapitulating HD symptoms. Objective: Manifest HD is currently diagnosed upon the onset of motor symptoms, thus we sought to longitudinally characterise the progression and severity of motor signs in the Hdh Q111 knock-in mouse …model of HD, in heterozygous mice. Methods: An extensive battery of motor tests including: rotarod, inverted lid test, balance beam, spontaneous locomotor activity and gait analysis were applied longitudinally to a cohort of Hdh Q111 heterozygous mice in order to progressively assess motor function. Results: A progressive failure to gain body weight was demonstrated from 11 months of age and motor problems in all measures of balance beam performance were shown in Hdh Q111 heterozygous animals in comparison to wild type control animals from 9 months of age. A decreased latency to fall from the rotarod was demonstrated in Hdh Q111 heterozygous animals in comparison to wild type animals, although this was not progressive with time. No genotype specific differences were demonstrated in any of the other motor tests included in the test battery. Conclusions: The Hdh Q111 heterozygous mouse demonstrates a subtle and progressive motor phenotype that begins at 9 months of age. This mouse model represents an early disease stage and would be ideal for testing therapeutic strategies that require elongated lead-in times, such as viral gene therapies or striatal transplantation. Show more

Keywords: Huntington’s disease, mouse model, motor characterisation and longitudinal

DOI: 10.3233/JHD-160191

Citation: Journal of Huntington's Disease, vol. 5, no. 2, pp. 149-161, 2016

Authors: Vodicka, Petr | Chase, Kathryn | Iuliano, Maria | Valentine, Dana T. | Sapp, Ellen | Lu, Boxun | Kegel-Gleason, Kimberly B. | Sena-Esteves, Miguel | Aronin, Neil | DiFiglia, Marian

Article Type: Research Article

Abstract: Background: Reducing mutant huntingtin (mHTT) in neurons may be a therapy for Huntington’s disease (HD). Elevating NUB1 protein reduced mHTT levels in cell and fly models of HD through a proteasome dependent mechanism. Objective: To examine the effects of augmenting NUB1 in HD mouse striatum on mHTT levels. Methods: Striata of HDQ175/Q7 mice were injected at 3 months of age with recombinant AAV2/9 coding for NUB1 or GFP under the control of the neuron specific human synapsin 1 promoter and examined 6 months post-injection for levels of huntingtin, the striatal markers DARPP32 and PDE10A, …the astrocyte marker GFAP, and the autophagy and mHTT aggregate marker P62 using immunolabeling of brain sections and Western blot assay of striatal subcellular fractions. Results: By Western blot human HD brain had only one of the two variants of NUB1 present in human control brain. In striatum of WT and HD mice NUB1 was localized in medium size neurons and enriched in the nucleus of large neurons. In the striatum of NUB1 injected HD mice, there was widespread neuronal distribution of exogenous NUB1 labeling and protein levels were ∼2.5-fold endogenous levels. DARPP32 and GFAP distribution and levels were unchanged but PDE10A levels were lower in crude homogenates and P62 was increased in nuclear enriched P1 fractions. Elevating NUB1 did not change levels of full-length mHTT or the number and size of mHTT (S830) positive nuclear inclusions. Conclusion: Findings suggest that increasing NUB1 protein in striatal neurons of HDQ175/Q7 mice in vivo may be relatively safe but is ineffective in reducing mHTT. Increased NUB1 expression in HD striatum alters PDE10A and P62 which are known to be influenced by mHTT. Show more

Keywords: Adeno-associated virus, aggregates, huntingtin, Huntington’s disease, neurodegeneration, NUB1, NUB1L, P62, striatum

DOI: 10.3233/JHD-160195

Citation: Journal of Huntington's Disease, vol. 5, no. 2, pp. 163-174, 2016

Authors: Philpott, April L. | Andrews, Sophie C. | Staios, Mathew | Churchyard, Andrew | Fisher, Fiona

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an inherited neurodegenerative disorder characterised by motor, cognitive and neuropsychiatric symptoms. Recent research has established that individuals with HD display reduced discrimination of emotional facial expressions and impaired higher-order social cognitive skills, including ‘theory of mind’. Objective: This study aimed to further characterise the emotion evaluation and theory of mind deficits in HD in an ecologically-valid context, and determine their impact on socially-relevant functional abilities. Methods: A sample of 17 HD participants and 24 healthy controls were assessed using The Awareness of Social Inference Test (TASIT), together with additional self- …and informant rated measures of cognition, social communication, empathy and neuropsychiatric symptoms. Results: Participants with HD showed significant difficulties in evaluating negative emotions, and understanding sincere, sarcastic and ‘paradoxical sarcastic’ statements, compared with controls. The ability to evaluate positive emotions was negatively correlated with behavioural problems, but no other clinical, behavioural or communication measures correlated significantly with TASIT subscales. Conclusions: These findings suggest that social cognitive difficulties in symptomatic HD may be underpinned by more generalised impairments, related to deciphering social exchanges, as opposed to a selective theory of mind deficit. Such difficulties have the potential to place significant strain on interpersonal relationships, and thus warrant thorough clinical assessment, using ecologically-valid tools, to promote early detection and development of person-centred interventions. Show more

Keywords: Social cognition, theory of mind, TASIT, emotion recognition, sarcasm, executive function, social communication, empathy, clinical assessment

DOI: 10.3233/JHD-160190

Citation: Journal of Huntington's Disease, vol. 5, no. 2, pp. 175-183, 2016

Authors: Hubers, Anna A.M. | Hamming, Annette | Giltay, Erik J. | von Faber, Margaret | Roos, Raymund A.C. | van der Mast, Rose C. | van Duijn, Erik

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) mutation carriers are at increased risk of suicidal ideation, suicide attempts, and completed suicide. However, research is lacking on coping strategies and treatment options that can be offered to suicidal HD mutation carriers. Objective: This study explores how individuals with pre-motor or motor symptomatic HD cope with suicidality, how their partners support them, and their ideas and wishes regarding how relatives and healthcare professionals can help them in coping with suicidality. Methods: This qualitative study included 11 HD mutation carriers who experienced suicidal ideation or attempted suicide and 3 of their …partners. They participated in a focus group discussion or an individual in-depth interview. Two independent researchers fragmented the transcribed interviews, coded these fragments, grouped them under themes, and structured the data. Results: HD study participants used four main strategies to cope with suicidality, including talking about suicidality, employing self-management activities, using medication, and discussing end-of-life wishes. Partners, relatives, and healthcare professionals can support suicidal HD mutation carriers in each of those four strategies. Conclusions: Despite the absence of a turnkey solution for suicidality in HD, healthcare professionals can play an important role in supporting suicidal HD mutation carriers by providing an opportunity to talk about suicidality, providing psychoeducation on self-management, prescribing medication, and discussing end-of-life wishes. Future HD-specific intervention studies could investigate the effect of combining these treatment strategies into one holistic approach. Show more

Keywords: Neurodegenerative diseases, suicide, psychopathology, coping behaviour, therapy, qualitative research

DOI: 10.3233/JHD-160188

Citation: Journal of Huntington's Disease, vol. 5, no. 2, pp. 185-198, 2016

Authors: Andrzejewski, Kelly L. | Dowling, Ariel V. | Stamler, David | Felong, Timothy J. | Harris, Denzil A. | Wong, Cynthia | Cai, Hang | Reilmann, Ralf | Little, Max A. | Gwin, Joseph T. | Biglan, Kevin M. | Dorsey, E. Ray

Article Type: Research Article

Abstract: Background: The Unified Huntington’s Disease Rating Scale (UHDRS) is the principal means of assessing motor impairment in Huntington disease but is subjective and generally limited to in-clinic assessments. Objective: To evaluate the feasibility and ability of wearable sensors to measure motor impairment in individuals with Huntington disease in the clinic and at home. Methods: Participants with Huntington disease and controls were asked to wear five accelerometer-based sensors attached to the chest and each limb for standardized, in-clinic assessments and for one day at home. A second chest sensor was worn for six additional days at …home. Gait measures were compared between controls, participants with Huntington disease, and participants with Huntington disease grouped by UHDRS total motor score using Cohen’s d values. Results: Fifteen individuals with Huntington disease and five controls completed the study. Sensor data were successfully captured from 18 of the 20 participants at home. In the clinic, the standard deviation of step time (time between consecutive steps) was increased in Huntington disease (p  < 0.0001; Cohen’s d  = 2.61) compared to controls. At home with additional observations, significant differences were observed in seven additional gait measures. The gait of individuals with higher total motor scores (50 or more) differed significantly from those with lower total motor scores (below 50) on multiple measures at home. Conclusions: In this pilot study, the use of wearable sensors in clinic and at home was feasible and demonstrated gait differences between controls, participants with Huntington disease, and participants with Huntington disease grouped by motor impairment. Show more

Keywords: Huntington disease, remote sensing technology, clinical study, movement, gait, chorea, ambulatory monitoring

DOI: 10.3233/JHD-160197

Citation: Journal of Huntington's Disease, vol. 5, no. 2, pp. 199-206, 2016

Authors: Frich, Jan C. | Rae, Daniela | Roxburgh, Richard | Miedzybrodzka, Zofia H. | Edmondson, Mary | Pope, Erika Bjorklund | Goodman, LaVonne | Haddad, Monica S. | Giuliano, Joe | Nelson, Eugene C. | Guttman, Mark | Nance, Martha

Article Type: Research Article

Abstract: Background: Little is known about the organization of clinical services for Huntington’s disease (HD). Objective: To describe how health care services are organized and delivered in HD-clinics taking part in or eligible for the Enroll-HD study. Methods: In 2014, a 69-item survey was administered to sites taking part in or eligible for the Enroll-HD study. Results: Of 231 sites surveyed, 121 (52.2%) sites in Europe, North America, Latin America, and Oceania responded. Most sites in the sample serve large populations, with 61.1% serving more than 1.5 million people, and a further 33% serving …>500,000. Almost all (86.0%) centers see patients from outside their region. The majority of centers (59.7%) follow 50–199 patients, 21.9% care for more than 200. Most centers provide care in all stages of HD, and nearly all review pre-symptomatic cases. Multidisciplinary case reviews are offered in 54.5% of sites, with outreach clinics offered by 48.1%. Videoconferencing and telemedicine are used by 23.6%. Separate consultations for caregivers are offered in more than half of the centers. Most centers (70.4%) report following published guidelines or local care pathways for HD. Conclusions: Most centers serve a large population and use a multidisciplinary approach. The survey gives insight into factors underpinning HD service delivery globally. There is a need for more in-depth studies of clinical practice to understand how services are organized and how such features may be associated with quality of care. Show more

Keywords: Huntington’s disease, health services, quality of health care

DOI: 10.3233/JHD-160192

Citation: Journal of Huntington's Disease, vol. 5, no. 2, pp. 207-213, 2016

Article Type: Other

DOI: 10.3233/JHD-169002

Citation: Journal of Huntington's Disease, vol. 5, no. 2, pp. 215-216, 2016