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

Authors: Mazarei, Gelareh | Leavitt, Blair R.

Article Type: Review Article

Abstract: Within the past decade, there has been increasing interest in the role of tryptophan (Trp) metabolites and the kynurenine pathway (KP) in diseases of the brain such as Huntington’s disease (HD). Evidence is accumulating to suggest that this pathway is imbalanced in neurologic disease states. The KP diverges into two branches that can lead to production of either neuroprotective or neurotoxic metabolites. In one branch, kynurenine (Kyn) produced as a result of tryptophan (Trp) catabolism is further metabolized to neurotoxic metabolites such as 3-hydroxykunurenine (3-HK) and quinolinic acid (QA). In the other branch, Kyn is converted to the neuroprotective metabolite …kynurenic acid (KA). The enzyme Indoleamine 2,3 dioxygenase (IDO1) catalyzes the conversion of Trp into Kyn, the first and rate-limiting enzymatic step of the KP. This reaction takes place throughout the body in multiple cell types as a required step in the degradation of the essential amino acid Trp. Studies of IDO1 in brain have focused primarily on a potential role in depression, immune tolerance associated with brain tumours, and multiple sclerosis; however the role of this enzyme in neurodegenerative disease has garnered significant attention in recent years. This review will provide a summary of the current understanding of the role of IDO1 in Huntington’s disease and will assess this enzyme as a potential therapeutic target for HD. Show more

Keywords: Huntington’s disease, huntingtin, indoleamine 2,3 dioxygenase, kynurenine pathway, tryptophan, quinolinic acid

DOI: 10.3233/JHD-159003

Citation: Journal of Huntington's Disease, vol. 4, no. 2, pp. 109-118, 2015

Authors: Vaportzis, Eleftheria | Georgiou-Karistianis, Nellie | Churchyard, Andrew | Stout, Julie C.

Article Type: Research Article

Abstract: Background: Past research has found cancellation tasks to be reliable markers of cognitive decline in Huntington’s disease (HD). Objective: The aim of this study was to extend previous findings by adopting the use of a dual task paradigm that paired cancellation and auditory tasks. Methods: We compared performance in 14 early stage HD participants and 14 healthy controls. HD participants were further divided into groups with and without cognitive impairment. Results: Results suggested that HD participants were not slower or less accurate compared with controls; however, HD participants showed …greater dual task interference in terms of speed. In addition, HD participants with cognitive impairment were slower and less accurate than HD participants with no cognitive impairment, and showed greater dual task interference in terms of speed and accuracy. Conclusions: Our findings suggest that dual task measures may be a better measure of cognitive processing in HD compared with more traditional measures. Show more

Keywords: Attention allocation, divided attention, dual task, Huntington’s disease, visual search

DOI: 10.3233/JHD-140131

Citation: Journal of Huntington's Disease, vol. 4, no. 2, pp. 119-130, 2015

Authors: Tedroff, Joakim | Waters, Susanna | Barker, Roger A. | Roos, Raymund | Squitieri, Ferdinando | on behalf of the EHDN Registry Study Group

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder leading to progressive motor, cognitive and functional decline. Antidopaminergic medications (ADMs) are frequently used to treat chorea and behavioural disturbances in HD. Objective: We aimed to assess how the use of such medications was associated with the severity and progression of the motor aspects of the condition, given that there have been concerns that such drugs may actually promote neurological deterioration. Methods: Using multiple linear regression, supplemented by principal component analysis to explore the overall correlation patterns and help identify relevant covariates, …we assessed severity and progression of motor symptoms and functional decline in 651 manifest patients from the REGISTRY cohort followed for two years. ADM treated versus non-treated subjects were compared with respect to motor impairment at baseline and progression rate by means of multiple regression, adjusting for CAG-repeat and age. Results: Patients treated with ADMs had significantly worse motor scores with greater functional disability at their first visit. They also showed a higher annual rate of progression of motor signs and disability over the next two years. In particular the rate of progression for oculomotor symptoms and bradykinesia was markedly increased whereas the rate of progression of chorea and dystonia was similar for ADM and drug naïve patients. These differences in clinical severity and progression could not be explained by differences in disease burden, duration of disease or other possible prognostic factors. Conclusions: The results from this analysis suggest ADM treatment is associated with more advanced and rapidly progressing HD although whether these drugs are causative in driving this progression requires further, prospective studies. Show more

Keywords: Huntington disease, observational study, dopamine, antipsychotics, tetrabenazine

DOI: 10.3233/JHD-150143

Citation: Journal of Huntington's Disease, vol. 4, no. 2, pp. 131-140, 2015

Authors: Oosterloo, Mayke | Van Belzen, Martine J. | Bijlsma, Emilia K. | Roos, Raymund A.C.

Article Type: Research Article

Abstract: Background and Objective: Huntington’s disease (HD) is a neurodegenerative disease associated with a CAG repeat expansion in the Huntingtin (HTT) gene. A trinucleotide size between 27 and 35 is considered ‘intermediate’ and not to cause symptoms and signs of HD. There are articles claiming otherwise, however publishing only the cases that have a HD phenotype introduces a significant publication bias. Our objective is to determine if there is convincing evidence that intermediate repeats (IA) cause HD. Methods: Previously published case reports on HTT intermediate repeat sizes and all cases from the Netherlands with …an IA were reviewed for clinical symptoms and signs. Results: Four patients had a clinical presentation of Huntington’s disease and an IA out of ten reported cases in literature. Between 2001 and 2012, 1,690 patients were tested for HD in the Netherlands. One case out of 60 with an IA had a phenotype resembling HD, but had already been published in a case report. Conclusion: Given the high background frequency of intermediate alleles in several populations, the possibility of developing HD would have huge implications for 1–7% of the normal population. It is possible that IAs present as an endophenotype with the potential of subsequent clinical manifestations. However, given the scarcity of convincing cases, the lack of convincing biological evidence for pathogenicity of intermediate alleles, and many genes still to be discovered for HD mimics, we find that it is premature to claim that IAs can cause HD. We recommend systematic follow up of this group of individuals and if possible brain pathology for confirmation or exclusion of HD. Show more

Keywords: Trinucleotide repeat diseases, Huntington’s disease, Huntingtin gene, intermediate allele, intermediate CAG repeat

DOI: 10.3233/JHD-140120

Citation: Journal of Huntington's Disease, vol. 4, no. 2, pp. 141-148, 2015

Authors: Steventon, Jessica J. | Harrison, David J. | Trueman, Rebecca C. | Rosser, Anne E. | Jones, Derek K. | Brooks, Simon P.

Article Type: Research Article

Abstract: Background: Environmental enrichment has been shown to improve symptoms and reduce neuropathology in mouse models of Huntington’s disease (HD); however results are limited to ex vivo techniques with associated shortcomings. In-vivo magnetic resonance imaging (MRI) can overcome some of the shortcomings and is applied for the first time here to assess the effect of a cognitive intervention in a mouse model of HD. Objectives: We aimed to investigate whether in-vivo high-field MRI can detect a disease-modifying effect in tissue macrostructure following a cognitive enrichment regime. Methods: YAC128 transgenic and wild …type mice were exposed to cognitive enrichment throughout their lifetime. At 20-months old, mice were scanned with a T2 -weighted MRI sequence and a region-of-interest (ROI) approach was used to examine structural changes. Locomotor activity and performance on the rotarod and serial discrimination watermaze task were assessed to measure motor and cognitive function respectively. Results: Mice exposed to cognitive enrichment were more active and able to stay on a rotating rod longer compared to control mice, with comparable rotarod performance between HD enriched mice and wild-type mice. YAC128 mice demonstrated cognitive impairments which were not improved by cognitive enrichment. In-vivo MRI revealed a reduction in the degree of caudate-putamen atrophy in the enriched HD mice. Conclusions: We provide in vivo evidence of a beneficial effect of environmental enrichment on neuropathology and motor function in a HD mouse model. This demonstrates the efficacy of MRI in a model of HD and provides the basis for an in-vivo non-destructive outcome measure necessary for longitudinal study designs to understand the effect of enrichment with disease progression. Show more

Keywords: Huntington’s Disease, magnetic resonance imaging, cognitive enrichment, mouse model

DOI: 10.3233/JHD-150147

Citation: Journal of Huntington's Disease, vol. 4, no. 2, pp. 149-160, 2015

Authors: Mort, Matthew | Carlisle, Francesca A. | Waite, Adrian J. | Elliston, Lyn | Allen, Nicholas D. | Jones, Lesley | Hughes, Alis C.

Article Type: Research Article

Abstract: Background: A CAG repeat expansion in HTT has been known to cause Huntington’s disease for over 20 years. The genomic sequence of the 67 exon HTT is clear but few reports have detailed alternative splicing or alternative transcripts. Most eukaryotic genes with multiple exons show alternative splicing that increases the diversity of the transcriptome and proteome: it would be surprising if a gene with 67 known exons in its two major transcripts did not present some alternative transcripts. Objective: To investigate the presence of alternative transcripts directly in human HTT . …Methods: An overlapping RT-PCR based approach was used to determine novel HTT splice variants in human brain from HD patients and controls and 3D protein homology modelling employed to investigate their significance on the function of the HTT protein. Results: Here we show multiple previously unreported novel transcripts of HTT . Of the 22 splice variants found, eight were in-frame with the potential to encode novel HTT protein isoforms. Two splice variants were selected for further study; HTT Δex4,5,6 which results in the skipping of exons 4, 5 and 6 and HTTex41b which includes a novel exon created via partial retention of intron 41. 3D protein homology modelling showed that both splice variants are of potential functional significance leading to the loss of a karyopherin nuclear localisation signal and alterations to sites of posttranslational modification. Conclusions: The identification of novel HTT transcripts has implications for HTT protein isoform expression and function. Understanding the functional significance of HTT alternative splicing would be critical to guide the design of potential therapeutics in HD that aim to reduce the toxic HTT transcript or protein product including RNA silencing and correction of mis-splicing in disease. Show more

Keywords: Huntington’s disease, alternative splicing, RNA species, protein isoforms, structural modelling

DOI: 10.3233/JHD-150151

Citation: Journal of Huntington's Disease, vol. 4, no. 2, pp. 161-171, 2015

Authors: Heidari, Raheleh | Monnier, Véronique | Martin, Elodie | Tricoire, Hervé

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a Polyglutamine disease caused by the presence of CAG repeats in the first exon of Huntingtin (Htt), a large protein with multiple functions. In addition to neurodegeneration of specific brain regions, notably the striatum, HD also shows alterations in peripheral tissues, such as the heart, skeletal muscles or peripheral endocrine glands. Mutant Huntingtin (mHtt)-driven mitochondrial impairment may underlie some of the CNS and peripheral tissues dysfunctions, especially in tissues with high energy demand such as the heart. Objective: The aim of this study is to characterize two new inducible Drosophila …HD heart models and to assay the therapeutic potential of methylene blue in these HD models. Methods: We report the construction of inducible Drosophila HD heart models, expressing two Nter fragments of the protein encompassing either exon 1 or the first 171 amino acids and the characterization of heart phenotypes in vivo . Results: We show that both mHtt fragments are able to impair fly cardiac function with different characteristics. Additionally, expression of mHtt, which was limited to adulthood only, leads to mild heart impairment, as opposed to a strong and age-dependent phenotype observed when mHtt expression was driven during both developmental and adult stages. We report that treatment with methylene blue (MB), a protective compound in mitochondria-related diseases, partially protects the fly’s heart against mHtt-induced toxicity, but does not rescue neuronal or glial phenotypes in other fly models of HD. This may be linked to its low penetration through the fly’s blood-brain barrier. Conclusions: Our data suggest that improvement of mitochondrial function by MB, or related compounds, could be an efficient therapeutic strategy to prevent cardiac failure in HD patients. Show more

Keywords: Drosophila, Huntington’s disease, SCA3, heart, methylene blue

DOI: 10.3233/JHD-140130

Citation: Journal of Huntington's Disease, vol. 4, no. 2, pp. 173-186, 2015

Authors: Vodicka, Petr | Mo, Shunyan | Tousley, Adelaide | Green, Karin M. | Sapp, Ellen | Iuliano, Maria | Sadri-Vakili, Ghazaleh | Shaffer, Scott A. | Aronin, Neil | DiFiglia, Marian | Kegel-Gleason, Kimberly B.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG expansion in the HD gene, which encodes the protein Huntingtin. Huntingtin associates with membranes and can interact directly with glycerophospholipids in membranes. Objective: We analyzed glycerophospholipid profiles from brains of 11 month old wild-type (WT) and Q140/Q140 HD knock-in mice to assess potential changes in glycerophospholipid metabolism. Methods: Polar lipids from cerebellum, cortex, and striatum were extracted and analyzed by liquid chromatography and negative ion electrospray tandem mass spectrometry analysis (LC-MS/MS). Gene products involved in polar lipid metabolism were studied …using western blotting, immuno-electron microscopy and qPCR. Results: Significant changes in numerous species of glycerophosphate (phosphatidic acid, PA) were found in striatum, cerebellum and cortex from Q140/Q140 HD mice compared to WT mice at 11 months. Changes in specific species could also be detected for other glycerophospholipids. Increases in species of lyso-PA (LPA) were measured in striatum of Q140/Q140 HD mice compared to WT. Protein levels for c-terminal binding protein 1 (CtBP1), a regulator of PA biosynthesis, were reduced in striatal synaptosomes from HD mice compared to wild-type at 6 and 12 months. Immunoreactivity for CtBP1 was detected on membranes of synaptic vesicles in striatal axon terminals in the globus pallidus. Conclusions: These novel results identify a potential site of molecular pathology caused by mutant Huntingtin that may impart early changes in HD. Show more

Keywords: Huntington’s disease, Huntingtin, glycerophospholipid, mass spectrometry, phosphatidic acid, acyl transferase, lipidomics, CtBP, LPAAT, phospholipase, LPA

DOI: 10.3233/JHD-150149

Citation: Journal of Huntington's Disease, vol. 4, no. 2, pp. 187-201, 2015

Article Type: Meeting Report

DOI: 10.3233/JHD-159002

Citation: Journal of Huntington's Disease, vol. 4, no. 2, pp. 203-203, 2015