Huntington's Chorea Research Articles

A Role of GABA Analogues in the Treatment of Neurological Diseases

gamma-Amino butyric acid is an extremely important inhibitory neurotransmitter in the mammalian central nervous system and is essential for the overall balance between neuronal excitation and inhibition. It is well documented that GABA deficiency is associated with several important neurological disorders such as Huntington's chorea, Parkinson's and Alzheimer's disease and other psychiatric disorders, like anxiety, depression, pain, panic, or mania. Although, it is known that increasing the brain concentration of GABA prevents convulsions, the high polarity and flexible structure of this compound are probably responsible for its inefficiency as an anticonvulsant when administered orally or intravenously. To resolve this problem, GABA analogues are being designed. Over recent years, there has been increasing interest in the synthesis and pharmacological effect of new GABA derivatives, which can be considered as potent drugs in the treatment of neurodegenerative disorders.

What do the basal ganglia do? A modeling perspective

Basal ganglia (BG) constitute a network of seven deep brain nuclei involved in a variety of crucial brain functions including: action selection, action gating, reward based learning, motor preparation, timing, etc. In spite of the immense amount of data available today, researchers continue to wonder how a single deep brain circuit performs such a bewildering range of functions. Computational models of BG have focused on individual functions and fail to give an integrative picture of BG function. A major breakthrough in our understanding of BG function is perhaps the insight that activities of mesencephalic dopaminergic cells represent some form of 'reward' to the organism. This insight enabled application of tools from 'reinforcement learning,' a branch of machine learning, in the study of BG function. Nevertheless, in spite of these bright spots, we are far from the goal of arriving at a comprehensive understanding of these 'mysterious nuclei.' A comprehensive knowledge of BG function has the potential to radically alter treatment and management of a variety of BG-related neurological disorders (Parkinson's disease, Huntington's chorea, etc.) and neuropsychiatric disorders (schizophrenia, obsessive compulsive disorder, etc.) also. In this article, we review the existing modeling literature on BG and hypothesize an integrative picture of the function of these nuclei.

Role of Tetrabenazine for Huntington's Disease-Associated Chorea

To review the pharmacology, pharmacokinetics, efficacy, and safety of tetrabenazine for the treatment of Huntington's disease (HD)-associated chorea. Primary literature and review articles were obtained through a PubMed search (1959-November 2009) using the terms tetrabenazine, HD, chorea, and hyperkinetic movement disorders. A bibliographic search was performed on selected articles. All English-language articles identified from the data sources were reviewed. Studies including greater than 10 patients and a direct comparative study with primarily HD-associated chorea were included in the review. Tetrabenazine is the first drug approved by the Food and Drug Administration (FDA) for the management of HD-associated chorea. Tetrabenazine binds reversibly to the type 2 vesicular monoamine transporters and has been shown to inhibit monoamine uptake in presynaptic vesicles, resulting in monoamine depletion. The duration of the antichorea effect of tetrabenazine has been reported to be approximately 5.5 hours. Tetrabenazine is extensively metabolized hepatically by the CYP2D6 enzyme to its primary active metabolite, alpha-dihydrotetrabenazine. The half-life of alpha-dihydrotetrabenazine is 4-8 hours. Clinical trials demonstrated that tetrabenazine reduces chorea, on average, by 5 units based upon the chorea score from the Unified Huntington's Disease Rating Scale. The most common adverse effects reported include sedation, drowsiness, parkinsonism, and depression. Rarely, corrected QT interval prolongation, orthostatic hypotension, and hyperprolactinemia have been reported. Tetrabenazine also has a black box warning for increasing the risk of depression and suicidality. Tetrabenazine can provide significant benefit in the treatment of chorea associated with HD. Given the potential adverse effects of tetrabenazine, health-care providers need to screen patients carefully prior to initiating treatment with this medication. In the future, additional long-term and comparative studies would be useful for further clarification of the role of tetrabenazine in the treatment of HD-associated chorea.

EPA and Huntington's chorea: treatment and associated cerebral changes

Huntington's disease (Huntington's chorea) is an autosomal dominant disease of the human brain caused by an unstable expansion of CAG trinucleotide triplet repeats in the huntingtin gene at 4p16.3; the CAG repeats are transcribed and translated into polyglutamine expansion (polyQ) stretches, and the length of the repeats correlates inversely with age of onset. Huntington's disease is characterized by motor dysfunction, with chorea and incoordination occurring relatively early and dystonia, rigidity and bradykinesia becoming more prominent with time; death usually occurs within 15-25 years of onset of motor symptomatology. The key neuropathological change is neuronal degeneration, particularly in the striatum. The scientific background is given for why fatty acids may play an important role in Huntington's disease. Evidence is then presented from a randomized double-blind placebo-controlled to show that ultra-pure ethyl-eicosapentaenoic acid (ethyl-EPA), a semi-synthetic, ethyl ester of eicosapentaenoic acid, is associated with clinical improvement in motor functioning in Huntington's disease. The likely mechanisms of this beneficial action are then described. Finally, the results are detailed of a further recent study to determine the extent to which ethyl-EPA might reduce the rate of progress of cerebral atrophy. High-resolution cerebral magnetic resonance imaging scans were acquired at baseline, six months and one year in up to 34 patients with stage I or II Huntington's disease who took part in the trial of ethyl-EPA. For each subject and each pair of structural images, the two-timepoint brain volume change was calculated in a double-blind manner.

The internal state of medium spiny neurons varies in response to different input signals

BackgroundParkinson's disease, schizophrenia, Huntington's chorea and drug addiction are manifestations of malfunctioning neurons within the striatum region at the base of the human forebrain. A key component of these neurons is the protein DARPP-32, which receives and processes various types of dopamine and glutamate inputs and translates them into specific biochemical, cellular, physiological, and behavioral responses. DARPP-32's unique capacity of faithfully converting distinct neurotransmitter signals into appropriate responses is achieved through a complex phosphorylation-dephosphorylation system that evades intuition and predictability.ResultsTo gain deeper insights into the functioning of the DARPP-32 signal transduction system, we developed a dynamic model that is robust and consistent with available clinical, pharmacological, and biological observations. Upon validation, the model was first used to explore how different input signal scenarios are processed by DARPP-32 and translated into distinct static and dynamic responses. Secondly, a comprehensive perturbation analysis identified the specific role of each component on the system's signal transduction ability.ConclusionsOur study investigated the effects of various patterns of neurotransmission on signal integration and interpretation by DARPP-32 and showed that the DARPP-32 system has the capability of discerning surprisingly many neurotransmission scenarios. We also screened out potential mechanisms underlying this capability of the DARPP-32 system. This type of insight deepens our understanding of neuronal signal transduction in normal medium spiny neurons, sheds light on neurological disorders associated with the striatum, and might aid the search for intervention targets in neurological diseases and drug addiction.

A Unified Rapid PCR Method for Detection of Normal and Expanded Trinucleotide Alleles of CAG Repeats in Huntington Chorea and CGG Repeats in Fragile X Syndrome

We report on a unified rapid betaine-based-PCR protocol for amplification of the (CAG)n region in Huntington disease (HD) and the (CGG)n region in Fragile X syndrome (FXS), followed by an electrophoretic separation on automated sequencer for precise determination of the triplet numbers. The high betaine concentration (2.5 M betaine) permits precise amplification of the CAG and CGG repeats. Ten HD affected patients and 10 healthy individuals from HD families were re-evaluated. For FXS the CGG region in normal individuals and premutations of about 100 repeats were precisely amplified by this protocol. Ten unrelated FXS premutation carriers and 24 mentally retarded non-FXS affected boys were re-examined by this method. The results totally coincided with the previous ones. This protocol is a good choice as a fast screening test. Within 24 h we can have preliminary information on the patient's genetic status. Normal individuals, CGG premutation carriers up to 100 repeats, as well as HD patients carrying an expansion up to 50 CAG repeats can be easily clarified. This accounts for a relatively large proportion (about 90%) of the suspected HD and FXS patients, referred to our laboratory for genetic analysis. The calculation of the repeat's number is more accurate for the correct interpretation of the results, screening tests and genetic counselling.

Hydrophobic Side Chain Dynamics of a Glutamate Receptor Ligand Binding Domain

Ionotropic glutamate receptors are ligand-gated ion channels that mediate much of the fast excitatory neurotransmission in the central nervous system. The extracellular ligand binding core (S1S2) of the GluR2 subtype of ionotropic glutamate receptors can be produced as a soluble protein with properties essentially identical to the corresponding domain in the intact, membrane-bound protein. Using a variety of biophysical techniques, much has been learned about the structure and dynamics of S1S2 and the relationship between its ligand-induced conformational changes and the function of the receptor. It is clear that dynamic processes are essential to the function of ionotropic glutamate receptors. We have isotopically labeled side chain methyls of GluR2 S1S2 and used NMR spectroscopy to study their dynamics on the ps-ns and mus-ms time scales. Increased disorder is seen in regions that are part of the key dimer interface in the intact protein. When glutamate is bound, the degree of ps-ns motion is less than that observed with other ligands, suggesting that the physiological agonist binds to a preformed binding site. At the slower time scales, the degree of S1S2 flexibility induced by ligand binding is greatest for willardiine partial agonists, least for antagonists, and intermediate for full agonists. Notable differences among bound ligands are in the region of the protein that forms a hinge between two lobes that close upon agonist binding, and along the beta-sheet in Lobe 2. These motions provide clues as to the functional properties of partial agonists and to the conformational changes associated with lobe closure and channel activation.

Research and applied medical genetics: filling the gap

Research and applied medical genetics: filling the gap

Directed Evolution Reveals Hidden Properties of VMAT, a Neurotransmitter Transporter

The vesicular neurotransmitter transporter VMAT2 is responsible for the transport of monoamines into synaptic and storage vesicles. VMAT2 is the target of many psychoactive drugs and is essential for proper neurotransmission and survival. Here we describe a new expression system in Saccharomyces cerevisiae that takes advantage of the polyspecificity of VMAT2. Expression of rVMAT2 confers resistance to acriflavine and to the parkinsonian toxin 1-methyl-4-phenylpyridinium (MPP(+)) by their removal into the yeast vacuole. This expression system allowed identification of a new substrate, acriflavine, and isolation of mutants with modified affinity to tetrabenazine (TBZ), a non-competitive inhibitor of VMAT2 that is used in the treatment of various movement disorders including Tourette syndrome and Huntington chorea. Whereas one type of mutant obtained displayed decreased affinity to TBZ, a second type showed only a slight decrease in the affinity to TBZ, displayed a higher K(m) to the neurotransmitter serotonin, but conferred increased resistance to acriflavine and MPP(+). A protein where both types of mutations were combined (with only three amino acid replacements) lost most of the properties of the neurotransmitter transporter (TBZ-insensitive, no transport of neurotransmitter) but displayed enhanced resistance to the above toxicants. The work described here shows that in the case of rVMAT2, loss of traits acquired in evolution of function (such as serotonin transport and TBZ binding) bring about an improvement in older functions such as resistance to toxic compounds. A process that has taken millions of years of evolution can be reversed by three mutations.

A comparative study of MAP2 immunostaining in areas 9 and 17 in schizophrenia and Huntington chorea

Increasing evidence suggests that there may be significant morphological changes in the neuropil of the dorsolateral prefrontal cortex in schizophrenia. A controversial issue surrounding these deficits in the cortical neuropil is the confounding effects of antipsychotic (neuroleptic) medication as well as the question of generality to psychiatric disorders. To begin to address these issues we examined brains from Huntington’s patients matched to a cohort of schizophrenics and controls. Many Huntington’s patients take neuroleptics similar to schizophrenics; therefore, by comparing the two groups to controls we can begin to determine if neuroleptics play a role in the deficits reported in schizophrenia. Using MAP2 immunohistochemistry and thionin staining eight matched triplets of Huntington, schizophrenia and control, in areas 9 and 17 layers III and V were analyzed. Our results confirmed previous published data showing a schizophrenia-associated decrease in MAP2 in area 9 with no change in area 17. Similarly the Huntington’s patients showed no change in area 9 layer III and no change in area 17. There was however, a modest decrease observed in layer V area 9 of the Huntington’s patients. Neuron density measurements showed no change in either layer or brain region in any of the diagnostic categories. These observations suggest that antipsychotic medication may not be responsible for some of the morphological changes observed in the neuropil of the PFC in schizophrenia.

Critical role of transglutaminase and other stress proteins during neurodegenerative processes

Proteolytic stress, resulting from the intracellular accumulation of misfolded or aggregated proteins, which exceed the capacity of the ubiquitin-proteasome system to degrade them, plays a relevant role in neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's chorea. Most of toxic protein aggregates are characterised by the presence of isopeptide bonds (cross-links) catalysed by transglutaminase activity; further, several disease-specific proteins-tau, amyloid-beta, alpha-synuclein, huntingtin-are in vitro and/or in vivo substrates of transglutaminase 2. These findings suggest an important role for transglutaminase 2-mediated cross-linking reactions in neurodegeneration. Therefore, the use of transglutaminase activity inhibitors could ameliorate neuronal cell death. New therapeutic perspectives also arise from the possibility to prevent or reduce protein aggregation by enhancing the activation of heat shock proteins, which have been shown to be potent suppressors of neurodegeneration in cell cultures/animal models. Interestingly, some heat shock proteins have been shown to be in vitro or in vivo cross-linked by transglutaminase 2. These observations seem to suggest that transglutaminase activity could be involved in the stabilization of intracellular protein aggregates by interfering with proteasomal degradation of misfolded proteins. Further studies are needed to validate leading hypotheses and to open new prospects for developing therapeutic tools.

P1.018 Neuroprotective effect of neuroimmunophilins against 3-nitropropionic acid induced Huntington's chorea like symptoms: possible cognitive dysfunction and biochemical and cellular alterations

P1.018 Neuroprotective effect of neuroimmunophilins against 3-nitropropionic acid induced Huntington's chorea like symptoms: possible cognitive dysfunction and biochemical and cellular alterations

Research With Cognitively Impaired Participants

Illnesses that cause cognitive impairment are a considerable health problem in the United States. These include Alzheimer's disease, Huntington's chorea, cerebrovascular disease, psychiatric disorders, chronic alcoholism, and AIDS dementia complex. Illness associated with cognitive impairment may cause great suffering to the affected patients and their families. Research involving individuals who may be at risk for or have cognitive impairment is necessary to improve our understanding of these illnesses. For example, this may occur during efforts to develop effective therapies to treat them. However, research with participants who have cognitive impairment presents additional ethical concerns because they may be vulnerable to coercion. Therefore, nurse researchers must not only understand the principles of informed consent (i.e., autonomy, beneficence, nonmaleficence, and justice), but also the additional safeguards provided in the common rule to protect cognitively impaired participants in research. These safeguards include advanced informed consent, legal representative, and assent. Gaps exist in federal regulations related to adhering to these safeguards such as how to assess for decision-making capacity and variations on who can be a legal representative. The nurse researchers have potential roles as educators and advocates in research involving participants with cognitive impairment.

Huntington's disease part 1: what is it?

This is the first in a two-part series on Huntington's disease (HD). Part one describes what the neurological disease is and how it affects sufferers. HD is a progressive genetic neurological disease which affects approximately 6.2 in 100000 adults within the UK (Orphanet, 2008). HD is a hereditary disorder of the central nervous system. It used to be known as Huntington's chorea. Huntington's disease usually develops in adulthood and can cause a very wide range of symptoms (Huntingdon's Disease Association, 2008).

Association and linkage studies of Huntington's chorea in relation to fifteen genetic markers.

A search for association and linkage was made between Huntington's chorea and the following marker systems: ABO, MN, Rh, P, K, Fy, Jk, Se, AcP, AK, PGM1, 6-PGD, Tf, Hp and Gc. An association was found between Huntington's chorea and the blood group phenotype Fy(a+). Preliminary analysis of the data did not indicate the presence of close linkage, but in view of the uncertainty of the final diagnosis of some healthy siblings it was deemed desirable to re-analyse the data in about 10 to 15 years time.

POSSIBLE PATHOGENESIS OF HUNTINGTON'S CHOREA AND A NEW APPROACH TO TREATMENT

Recent identification of glutamate as a transmitter in neocortical efferents and discovery of toxic effects of excessive amounts of extra-cellular glutamate or its analogues on some brain neurons offer an explanation of the pathogenesis of Huntington's chorea. Cell death as well as consequent biochemical changes and clinical symptoms in this disease possibly result from excessive excitation of the neostriatal, and of some other neurons by glutamate released from neocortical axon terminals. If so, the development of Huntington's chorea could be prevented or arrested by blockers of glutamate transmissions, and folate should be reduced to the minimum in the diet of the genetically marked families.

Free and conjugated CSF and plasma GABA in Huntington's chorea.

Free and conjugated GABA concentrations were measured in CSF and plasma from 28 patients with manifest Huntington's chorea (HC) and 30 age- and sex-matched controls. GABA was determined by ion-exchange chromatography with fluorimetric detection (IE/F). Free and conjugated CSF GABA was significantly decreased in prolonged HC with advanced disease states and was suggested practicable as an additional diagnostic tool. However, in younger patients (less than 40 yrs) with a short period of HC (less than 2 yrs) an overlap with the age-matched normal range indicated GABA measurement inadequate to early diagnosis nor predictive for offspring at risk. An age-dependent decrease of conjugated CSF GABA was observed in patients and controls. The more pronounced decrease in patients might reflect the neurodegenerative feature of HC.

Huntington's chorea: a prevalence study in the Florence area.

A prevalence study of Huntington's chorea in Florence area in the period 1970-1979. Two clusters have been identified and the frequency of subjects heterozygote for Huntington's gene has been determined for planning Public Health intervention and the preparation of correct genetic counselling.

Progabide in the treatment of hyperkinetic extrapyramidal movement disorders.

The ability of the selective GABA-receptor agonist, progabide, to suppress abnormal involuntary movements was evaluated in a preliminary open pilot study. 17 patients, 10 males and 7 females, aged 10-78 years, with hyperkinetic movement disorders were included in the study. Daily doses of progabide ranged from 900 to 3600 mg (median 2400 mg) corresponding to 14-45 mg/kg (median 45 mg/kg), while the duration of treatment varied from 2 to 52 weeks. Improvement, with a reduction of involuntary movements exceeding 25%, occurred in two of four patients with Gilles de la Tourette's syndrome, and in two of three patients with postanoxic intention myoclonus, while no consistent beneficial effects were registered in ten patients with Huntington's chorea, postanoxic choreoathetosis, torsion dystonia, tardive dyskinesia, action tremor, essential myoclonus, or oro-branchio-respiratory myoclonus.

Quantification of choreatic movements by Doppler radar.

A simple and effective method is described to quantify involuntary movements. The method is based on the Doppler radar principle. Reproducibility of the method is demonstrated in a group of patients with Huntington's chorea and Tardive Dyskinesia. It is shown that the method correlates with clinical assessments, but is preferable because of its objectivity and simplicity.