Journal of Huntington's Disease - Volume 7, issue 1

Authors: Waters, Susanna | Tedroff, Joakim | Ponten, Henrik | Klamer, Daniel | Sonesson, Clas | Waters, Nicholas

Article Type: Review Article

Abstract: Despite advances in understanding the pathophysiology of Huntington’s disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo …effect. This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo , pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD. Show more

Keywords: Huntington’s disease, pridopidine, prefrontal cortex, striatum, motor control, dopamine, stabilizer, indirect pathway, dopamine D2 receptors

DOI: 10.3233/JHD-170267

Citation: Journal of Huntington's Disease, vol. 7, no. 1, pp. 1-16, 2018

Authors: Kovalenko, Marina | Milnerwood, Austen | Giordano, James | St. Claire, Jason | Guide, Jolene R. | Stromberg, Mary | Gillis, Tammy | Sapp, Ellen | DiFiglia, Marian | MacDonald, Marcy E. | Carroll, Jeffrey B. | Lee, Jong-Min | Tappan, Susan | Raymond, Lynn | Wheeler, Vanessa C.

Article Type: Research Article

Abstract: Background: Successful disease-modifying therapy for Huntington’s disease (HD) will require therapeutic intervention early in the pathogenic process. Achieving this goal requires identifying phenotypes that are proximal to the HTT CAG repeat expansion. Objective: To use Htt CAG knock-in mice, precise genetic replicas of the HTT mutation in patients, as models to study proximal disease events. Methods: Using cohorts of B6J.HttQ 111 /+ mice from 2 to 18 months of age, we analyzed pathological markers, including immunohistochemistry, brain regional volumes and cortical thickness, CAG instability, electron microscopy of striatal synapses, and acute …slice electrophysiology to record glutamatergic transmission at striatal synapses. We also incorporated a diet perturbation paradigm for some of these analyses. Results: B6J.HttQ 111 /+ mice did not exhibit significant neurodegeneration or gliosis but revealed decreased striatal DARPP-32 as well as subtle but regional-specific changes in brain volumes and cortical thickness that parallel those in HD patients. Ultrastructural analyses of the striatum showed reduced synapse density, increased postsynaptic density thickness and increased synaptic cleft width. Acute slice electrophysiology showed alterations in spontaneous AMPA receptor-mediated postsynaptic currents, evoked NMDA receptor-mediated excitatory postsynaptic currents, and elevated extrasynaptic NMDA currents. Diet influenced cortical thickness, but did not impact somatic CAG expansion, nor did it show any significant interaction with genotype on immunohistochemical, brain volume or cortical thickness measures. Conclusions: These data show that a single HttQ 111 allele is sufficient to elicit brain region-specific morphological changes and early neuronal dysfunction, highlighting an insidious disease process already apparent in the first few months of life. Show more

Keywords: Huntington’s disease, mice, phenotypes, mutation, striatal synapses, immunohistochemistry, electron microscopy, electrophysiology, diet

DOI: 10.3233/JHD-170282

Citation: Journal of Huntington's Disease, vol. 7, no. 1, pp. 17-33, 2018

Authors: Wu, Jun | Ryskamp, Daniel | Birnbaumer, Lutz | Bezprozvanny, Ilya

Article Type: Research Article

Abstract: Background: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. We previously discovered that mutant Huntingtin sensitizes type 1 inositol 1,4,5-trisphosphate receptor (InsP3 R1) to InsP3 . This causes calcium leakage from the endoplasmic reticulum (ER) and a compensatory increase in neuronal store-operated calcium (nSOC) entry. We previously demonstrated that supranormal nSOC leads to synaptic loss in striatal medium spiny neurons (MSNs) in YAC128 HD mice. Objective: We sought to identify calcium channels supporting supranormal nSOC in HD MSNs and to validate these channels as potential therapeutic …targets for HD. Methods: Cortico-striatal cultures were established from wild type and YAC128 HD mice and the density of MSN spines was quantified. The expression of candidate nSOC components was suppressed by RNAi knockdown and by CRISPR/Cas9 knockout. TRPC1 knockout mice were crossed with YAC128 HD mice for evaluation of motor performance in a beamwalk assay. Results: RNAi-mediated knockdown of TRPC1, TRPC6, Orai1, or Orai2, but not other TRPC isoforms or Orai3, rescued the density of YAC128 MSN spines. Knockdown of stromal interaction molecule 1 (STIM1), an ER calcium sensor and nSOC activator, also rescued YAC128 MSN spines. Knockdown of the same targets suppressed supranormal nSOC in YAC128 MSN spines. These channel subunits co-immunoprecipitated with STIM1 and STIM2 in synaptosomal lysates from mouse striata. Crossing YAC128 mice with TRPC1 knockout mice improved motor performance and rescued MSN spines in vitro and in vivo , indicating that inhibition of TRPC1 may serve as a neuroprotective strategy for HD treatment. Conclusions: TRPC1 channels constitute a potential therapeutic target for treatment of HD. Show more

Keywords: Huntingtin, synaptic, store-operated calcium entry, TRPC1, STIM1, imaging, beamwalk

DOI: 10.3233/JHD-170266

Citation: Journal of Huntington's Disease, vol. 7, no. 1, pp. 35-50, 2018

Authors: Tsuang, Debby W. | Greenwood, Tiffany A. | Jayadev, Suman | Davis, Marie | Shutes-David, Andrew | Bird, Thomas D.

Article Type: Research Article

Abstract: Background: Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington’s disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD. Objective: To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD. Methods: DNA from subjects with HD and psychosis (HD+P; n  = 47), subjects with HD and no psychosis (HD-P; n  = 126), and controls (CTLs; n  = 207) was genotyped using …the Infinium PsychArray-24 v1.1 BeadChip. The allele frequencies of single-nucleotide polymorphisms (SNPs) that were previously associated with schizophrenia and related psychiatric disorders were compared between these groups. Results: Of the 30 candidate genes tested, 10 showed an association with psychosis in HD. The majority of these genes, including CTNNA2 , DRD2 , ERBB4 , GRID2 , GRIK4 , GRM1 , NRG1 , PCNT , RELN , and SLC1A2 , demonstrate network interactions related to glutamate signaling. Conclusions: This study suggests genetic associations between several previously identified candidate genes for schizophrenia and the occurrence of psychotic symptoms in HD. These data support the potential role of genes related to glutamate signaling in HD psychosis. Show more

Keywords: Delusions, genetic association studies, genetic predisposition to disease, genetics, glutamates, hallucinations, Huntington disease, modifier genes, psychotic disorders, schizophrenia

DOI: 10.3233/JHD-170277

Citation: Journal of Huntington's Disease, vol. 7, no. 1, pp. 51-59, 2018

Authors: Kielar, Catherine | Morton, A. Jennifer

Article Type: Research Article

Abstract: Background: The threshold of CAG repeat expansion in the HTT gene that causes HD is 36 CAG repeats, although ‘superlong’ expansions are found in individual neurons in post mortem brains. Previously, we showed that, compared to mice with <250 CAG repeats, disease onset in R6/2 mice carrying superlong (>440) CAG repeat expansions was delayed, and disease progression was slower. Inclusion pathology also differed from 250 CAG repeat mice, being dominated by a novel kind of extranuclear neuronal inclusion (nENNI) that resembles a class of aggregate seen in patients with the adult onset form of HD. Objective and …methods: Here, we characterised neuropathology in R6/2 mice with >400 CAG repeats using light and electron microscopy. Results: nENNIs were found with increased frequency and wider distribution with age. Some nENNIs appear to ‘mature’ as the disease develops, developing a multi-layered cored structure. Mice with superlong CAG repeats do not develop clinical signs until they are around 30–40 weeks of age, and they attain a normal life span (>2 years). Nevertheless, they show brain atrophy and unequivocal neuron loss from the striatum and cortex by 22 weeks of age, an age at which similar pathology is seen in 250 CAG repeat mice. Conclusions: Since this time-point is ‘end stage’ for a 250 CAG mouse, but very far (at least 18 months) from end stage for a > 440 CAG repeat mouse, our data confirm that the appearance of clinical signs, the formation of inclusions, and neurodegeneration are processes that progress independently. A better understanding of the relationship between CAG repeat length, neurodegenerative pathways, and clinical behavioural signs is essential, if we are to find strategies to delay or reverse the course of this disease. Show more

Keywords: nENNI, NII, extranuclear inclusions, aggregation, huntingtin, ubiquitin, neurodegeneration, electron microscopy

DOI: 10.3233/JHD-170265

Citation: Journal of Huntington's Disease, vol. 7, no. 1, pp. 61-76, 2018

Authors: Solberg, Olga Karin | Filkuková, Petra | Frich, Jan C. | Feragen, Kristin J. Billaud

Article Type: Research Article

Abstract: Background: The literature offers discrepant findings regarding age at death in individuals with Huntington disease (HD). Objective: To study the age at death and causes of death in males and females with a diagnosis of HD in Norway. Methods: Registry study of deaths in 1986–2015 using data from two national registries: the Norwegian Cause of Death Registry (NCDR) and the registry of the Centre for Rare Disorders (CRD), Oslo University Hospital. Results: Mean age at death for individuals with HD was found to be 63.9 years (NCDR) and 61.7 years (CRD), compared to a …mean of 76.9 years in the general population (NCDR). There were no significant gender differences for age at death in individuals with HD. The significant increase in age at death within the general population from 1986 to 2015 was not observed in individuals with HD. In 73.5% of individuals with HD, the underlying cause of death was HD, followed by cardiovascular diseases, cancer and respiratory diseases. The most common immediate cause of death was respiratory diseases (44.2%). Suicide was a more common cause of death in the population with HD (2.3%) compared to the general population (1.3%). Conclusion: The age at death of individuals with HD was stable over a period of 30 years and 13.3 years lower than in the general population. Longer life expectancy for females from the general population was not found in females with HD. Suicide was more common among individuals with HD compared to the general population. Show more

Keywords: Age at death, causes of death, Huntington disease, suicide

DOI: 10.3233/JHD-170270

Citation: Journal of Huntington's Disease, vol. 7, no. 1, pp. 77-86, 2018

Authors: Thompson, Leslie | Leavitt, Blair R.

Article Type: Editorial

DOI: 10.3233/JHD-189000

Citation: Journal of Huntington's Disease, vol. 7, no. 1, pp. 87-87, 2018

Authors: Rodrigues, Filipe B. | Wild, Edward J.

Article Type: Research Article

Abstract: In the second edition of the Huntington’s Disease Clinical Trials Corner we list all currently registered and ongoing clinical trials, summarise the top-line results of the recently-announced IONIS-HTTRX trial (NCT02519036), expand on Wave Life Sciences’ PRECISION-HD1 (NCT03225833) and PRECISION-HD2 (NCT03225846), and cover one recently finished trial: the FIRST-HD deutetrabenazine trial (NCT01795859).

Keywords: Huntington disease, clinical trials

DOI: 10.3233/JHD-189001

Citation: Journal of Huntington's Disease, vol. 7, no. 1, pp. 89-98, 2018

Article Type: Meeting Report

DOI: 10.3233/JHD-189002

Citation: Journal of Huntington's Disease, vol. 7, no. 1, pp. 99-99, 2018