The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1α) is a regulator of mitochondrial biogenesis and function and is decreased in the striatum of patients with Huntington’s Disease (HD). HD is an autosomal dominant neurological disorder caused by a polyglutamine repeat in the huntingtin protein which leads to degeneration of striatal and cortical tissues. PGC-1α undergoes targeted downregulation by mutant huntingtin protein (mtHtt) and PGC-1α knockout mice have striatal lesions similar to HD transgenic mice. Exogenous PGC-1α partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons while in vivo administration of PGC-1α to the striatum in a mouse model of HD reduces neuronal volume loss. Synaptic N-methyl-D-aspartate receptor (NMDAR)- activity can drive the expression of PGC-1α which is neuroprotective against oxidative and excitotoxic stress in vitro whereas extrasynaptic NMDAR expression is increased in HD. Excessive NMDAR activity, specifically through extrasynaptic rather than synaptic NMDARs, leads to excitotoxic death in neurons and its regulation has been targeted in the search for therapeutic interventions for multiple neurological disorders. The data presented in this thesis show that the repression of PGC-1α by mtHtt may be significant in the dysregulation of NMDARs in HD. Both PGC-1α knockdown and mutant huntingtin are found to increase extrasynaptic NMDAR activity and excitotoxicity in a non-additive way, suggesting common regulatory mechanisms. Furthermore exogenous PGC- 1α expression is sufficient to reverse this increase in extrasynaptic NMDAR currents and excitotoxicity by mtHtt. This thesis adds mechanistic insight into previous understanding of the synergistic roles of mtHtt, NMDAR activity and PGC-1α in HD. Finally, we show that chronic knockout of PGC-1α in the PGC-1α(-/-) mouse causes distinct alterations in glutamatergic signaling that do not mimic the observation of acute knockdown of PGC-1α. We propose that the loss of PGC-1α in a number of neurological disorders contributes to concurrent increases in aberrant glutamate signaling and excitotoxicity in these diseases.

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder of typically mid-life onset, for which there is currently no cure. HD is one of nine neurological disorders caused by the expansion of a CAG trinucleotide repeat that encodes an extended polyglutamine tract within the respective disease proteins (which, in the case of HD, is Huntingtin). Curiously, despite these proteins having mostly widespread patterns of expression in the brain, a specific subset of neurons is preferentially affected in each disease, whilst other neurons also expressing the mutant protein are relatively unaffected. Furthermore, although the expression patterns of these disease proteins often overlap in distribution within the brain, the population of neurons that is most vulnerable differs from one disease to the next. Knowledge of what determines the specificity of neuronal vulnerability is likely to provide insight into the molecular mechanism(s) underlying the pathology in these diseases. The aim of this work was to use the zebrafish model organism to investigate two factors hypothesised to contribute to the specificity of neuronal vulnerability in HD: 1) region-specific somatic expansion of the disease allele, and 2) disruption of normal Huntingtin (Htt) protein function. The most significant findings of this study resulted from the investigation into the normal function of Htt. Antisense morpholino oligonucleotides were used to specifically knock down Htt expression in early zebrafish development, resulting in a wide variety of developmental defects. Most notably, Htt-deficient zebrafish had pale blood due to a decrease in haemoglobin production, despite the presence of (apparently unavailable) iron within these cells. Provision of additional iron in a bio-available form to the cytoplasm restored haemoglobin production in Htt-deficient embryos. Since blood cells acquire iron via receptor-mediated endocytosis of transferrin, these results suggest a role for Htt in the release of iron from endocytic compartments into the cytosol. Iron is required for the function of many cellular proteins and enzymes that play key roles in oxidative energy production. Disrupted iron homeostasis and decreased energy metabolism are features of HD pathogenesis that correlate to the major sites of degeneration in the HD brain. The findings of this study raise the possibility that perturbation of normal Htt function (by polyglutamine expansion) may contribute to these defects, thereby providing a novel link between Htt function and specificity of neuronal vulnerability in HD. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1274748 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

Compared with saline injected controls, rats with bilateral injections of kainic acid (KA) in the dorsal striatum showed temporary aphagia and adipsia, long-lasting body weight decreases, increased locomotor response to d-amphetamine, increased spontaneous nocturnal locomotor activity, increased resistance to extinction, impaired acquisition and retention of avoidance behavior and increased latencies to leave start boxes in various mazes. The KA injections resulted in loss of local neurons in the dorsal striatum, with no appreciable damage either to dopaminergic terminals or to extrinisic myelinated axons, thus supporting both the selective neurotoxic action of KA on neuronal perikarya and the proposed similarity of KA-induced striatal lesions with those found in the caudate-putamen of patients with Huntington's disease (HD). The present results demonstrate that KA striatal lesioned rats also show behavioral and pharmacological similarities with HD patients. In addition, they support the view that HD is characterized by a "subcortical dementia syndrome". A review of HD is also presented. / Medicine, Faculty of / Graduate

Bakgrund: Huntingtons sjukdom (HS) är en neurologisk sjukdom som är genetiskt ärftlig och drabbar både kvinnor och män i lika stor utsträckning. Sjukdomen angriper nervcellerna i hjärnan som styr muskelregleringen, vilket leder till ofrivilliga rörelser. Kognitiv påverkan är ett annat symtom, liksom att talet och andningen påverkas. HS är en fortskridande sjukdom och indelas i olika faser. I den sista fasen är den drabbade helt beroende av andra. Sjukdomen brukar kallas för en anhörigsjukdom på grund av att det är de anhöriga som ofta intar vårdrollen till personen med HS. Syfte: Syftet var att beskriva hur anhörigvårdare till personer med Huntingtons sjukdom upplever sin livssituation, samt att beskriva de inkluderade vetenskapliga artiklarnas undersökningsgrupp. Metod: En beskrivande litteraturstudie baserad på tio vetenskapliga artiklar med kvalitativ ansats. Databaserna som användes till litteratursökningen var Cinahl och PsycINFO. Huvudresultat: Anhörigvårdare till personer med Huntingtons sjukdom beskrev en känslomässig stress som ofta ledde till depression och isolering. Deras liv blev åsidosatta då vårdandet upptog det mesta av deras tid samt att de kände sig ensamma i sin situation. Rädslan att själv drabbas var överhängande. Oförståelse och okunskap mötte dem ofta på vägen, både från sjukvårdspersonal och omgivning. Att erhålla stöd från familj, vänner och stödgrupper var betydelsefullt och önskvärt. Slutsatser: Anhörigvårdarna upplevde en känslomässig påfrestning genom vårdandet av sin familjemedlem med Huntingtons sjukdom. Sjuksköterskor bör ta lärdom av deras upplevelser för att förbättra vårdarbetet och bemötandet gentemot anhörigvårdarna. / Background: Huntington’s disease (HD) is a neurologic disease that’s genetic hereditary and can affect both women and men equally. The disease infect nerve cells in the brain that controls muscle regulation, leading to involuntary movements. Cognitive loss is another symptom, as well as influenced speech and breathing. HD is a progressive disease and is divided into various phases. In the last phase the victim is completely dependent on others. The disease is called a relative’s disease because the relative often takes the care role to the person with HD. Purpose: The aim of this study was to describe how family caregivers to persons with Huntington’s disease experience their situation in life. Furthermore to describe the included scientific articles study group. Method: A descriptive literature study based on ten scientific articles with qualitative approach. The databases used for the literature research were Cinahl and PsycINFO. Main results: Family carers of people with Huntington's disease described an emotional stress that often led to depression and isolation. Their lives were sidelined while caring occupied most of their time and they often felt alone in their situation. The fear of being affected themselves by the disease was imminent. Incomprehension and ignorance were common, both from the medical staff and the surroundings. Obtaining support from family, friends and support groups were significant and desirable. Conclusion:  Family carers experienced an emotional strain while caring for their family member with Huntington's disease. Nurses should learn from their experiences to improve nursing care and treatment against family carers.

Pas de résumé français / In this thesis, we investigated troubles of sentence processing in Huntington’s disease (HD) at earlystage, which represents a model of damage mainly confined to the striatum. The role of striatalstructures in sentence processing is agreed upon, but its nature is still controversial. Most studieshave reported a role of the striatum for complex sentences or more controlled processes withinsentence processing, but the interpretation of this pattern differs according to two main views.Some authors have proposed that striatal structures have a linguistic function restricted to somesub-processes of sentence processing, while others claim that the deficits detected depend on themodulation that executive function exerts on language and sentence processing. Here, we aimed atfilling the gap between these approaches by using a psycholinguistic perspective to investigate onthe one hand the role of executive functions, in particular, working memory, in sentenceprocessing, and on the other hand the nature of the linguistic discrepancies reported in associationto striatal lesions. We thus built experimental paradigms that allow dissociating fine-grainedlinguistic variations in healthy subjects, and transferred them to HD patients. The profile ofimpairment detected in our experiments showed that working memory and other sources ofcomplexity can interfere with sentence processing by decreasing accuracy, but an impairment ofspecific syntactic processes occurs when working memory is controlled for. The pattern of the finegrainedsyntactic impairment detected is consistent with a dissociation between more frequent/lesscontrolled (default) and less frequent/more controlled (non-default) procedures in sentenceprocessing. Additionally, we detected that this deficit occurs despite the fact that HD patients arestill able to process syntactic information, suggesting that striatal structures spare syntacticrepresentations while they are involved in correctly applying syntactic procedures in non-defaultcontexts. We propose that this pattern is explained by a role of striatal structures in selectingbetween competing alternatives during sentence processing, which results in an inability to adapt tothe sentence context for non-default procedures. This parallels the role of striatal structures for selecting between competing alternatives in order to adapt to the changing environment, as reportedin motor control and in other domains of cognition. Although the domain specificity of striatalinvolvement in language cannot be demonstrated, it is highly compatible with the results obtainedin this thesis. Hence, linguistic functions might be modulated by distinct cortico-striatal circuits: onthe one hand by selecting linguistic representations as a function of the context, and on the otherhand, by modulating performance in language through executive functions. The frameworkemerging from this work thus helps conciliating apparently incongruent findings reported in theliterature. Yet, future research should better characterize anatomo-functional correlates of thisproposal

Huntington’s disease (HD) is a heritable, neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. The progressive disease is caused by an unstable CAG expansion within the gene that normally encodes for the huntingtin protein (Htt). The expanded mutant form of Htt (mHtt) is expressed ubiquitously throughout patients’ bodies; however, neuronal degeneration is prominent only in the corpus striatum and, to a lesser extent, the cortex. The Ras homolog Rhes is also preferentially localized to the striatum. The putative co-factor Rhes has been shown to act with mHtt to cause neuronal death. Simvastatin, a lipid lowering drug, and zoledronate, a nitrogen bisphosphonate, act on the mevalonate pathway, which gives both Rhes and its target cells, binding sites. The current study aimed to interrupt the mevalonate pathway and inactivate, via de-prenylation, Rhes in CD-1 mice exposed to 3-nitroproprionic acid, a neurotoxin that mimics HD mitochondrial dysfunction and striatal degeneration. Results suggest that drug treatment does not rescue motor impairments and may potentiate 3-NP damage. The persistent motor deficits are discussed in relation to possible Rhes de-prenylation.

Social science research on third sector organisations in the last two decades has emphasised their growing presence and importance in healthcare. This has occurred alongside significant reorganisation of health systems in the UK, including a continued policy emphasis on partnership-working between the public sector and the third sector. However, unanswered questions in the literature remain with regard to the specific roles that these organisations fulfil within partnership arrangements. This thesis examines the role of third sector organisations within Scottish services for the chronic, neurodegenerative condition Huntington’s disease (HD). The closely connected nature of Scottish healthcare and the multitude of professionals involved in HD mean these services are an important, but currently understudied, example of professional interaction around complexity. A multi-methods qualitative research framework was used to gather perspectives of key individuals working in the Scottish HD and wider health scene. Making use of the key concepts of expertise and boundary work, this thesis argues that third sector organisations have an extensive shaping role in 1) the positioning of healthcare organisations, 2) the identities of healthcare professionals, and 3) the meanings around illness and the remit of support. The research findings revealed that organisations and professionals in HD partnership arrangements engaged in processes of boundary work in the negotiation of the roles of themselves and others. Third sector professionals occupied many positions within services, as both experts and supporters of patients. In the process they and other professionals often took on identities as ‘key, committed professionals’. Understanding around HD was also shaped by these professionals as the wider aspects of illness and its support were brought into focus. Building on these findings, it is argued that third sector professionals in coordination roles are well placed to develop a type of expertise that I term ‘aggregate know-how’ (Pols 2014), based around both their professional skills and their extensive contact with patient experiential knowledge. The research builds on and extends influential previous models of third sector ‘partnership’ in healthcare (Rabeharisoa 2003), emphasising the key role of third sector organisations in knowledge production. It also offers insights of both theoretical and practical use with regard to service delivery in healthcare, showing the potential for genuine third sector/public sector partnership around expertise when there is adequate cultural support and resources.

Huntington’s disease (HD) patients have been found to have specific deficits in emotional processing, most consistently demonstrating impairment recognizing the emotion expressed on a static face. The purpose of this study was to examine emotional memory in HD, which has not yet been investigated, and its relationship with executive functioning, emotional facial recognition, and the disease progression in HD. An emotional memory task with pleasant, neural, and unpleasant words was administered to control (n=26), prodromal HD (n=26), and manifest HD (n=29) participants in addition to executive function measures, an apathy scale, and emotional facial recognition task. Free recall was not significantly different between groups. Using recognition sensitivity (d’), prodromal HD participants did not demonstrate emotional memory enhancement, while manifest HD patients evidenced significantly lower emotional recognition relative to controls. Groups were significantly different on neutral word recognition. Emotional recognition sensitivity was related to disease progression, emotional facial recognition, and executive functioning, but not apathy. Regression models suggested that recognition for pleasant and unpleasant words have both shared and unique predictors, with executive dysfunction predicting affective recognition within both valences. Disease progression uniquely predicted unpleasant recognition while age was a negative predictor of pleasant recognition. These results suggest that impaired emotional memory is present in HD, progresses with the disease, and may evidence increased difficulty with negative emotional memory.

Amino acids and other ninhydrin-positive compounds were measured in post-mortem thalamus from 25 Huntington's choreics, 10 schizophrenics, 5 schizophrenic-like psychotics, and 23 controls dying without neurological disease. Gamma-aminobutyric acid (GABA) was significantly reduced in choreic thalami, in accord with deficiencies found in other brain regions choreics (Perry et al., 1973a,b). GABA was also significantly reduced in schizophrenic thalami, suggesting a biochemical link between these two diseases, and supporting the hypothesis of a defect in the GABA system in schizophrenia (Roberts, 1972). Homocarnosine, a GABA-containing dipeptide, was also low in choreic and 9 out of 10 schizophrenic thalami. One schizophrenic had extremely high homocarnosine. Glycerophosphoethanolamine was significantly elevated in Huntington's choreics, but not in schizophrenics. A number of other variables were considered for their potential influence on amino acid concentrations in thalamus. The majority of amino acids were found to rise in a significantly linear fashion in the interval 3 to 49 hours post-mortem, although other models might have described the change better. GABA, ornithine, histidine and tyrosine were found to decrease significantly with increasing age between 21 and 80 years, in controls. The effects of pre-mortem hypoxia, regional variation within the thalamus, and neuroleptic drug treatment could not be rigorously tested with these data. Neuroleptics were unlikely to have been the cause of group differences in GABA concentration, since they failed to deplete GABA in brain of chronically treated rats. On the other hand, bronchopneumonia and other causes of pre-mortem hypoxia could not be ruled out as potential contributers to reduced GABA in thalamus. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

Huntingtons sjukdom (HS) är en ovanligt förekommande sjukdom med komplexa sjukdomsförlopp. Att vara anhörigvårdare till en individ som drabbats av HS kan därför innebära en speciellt utmanande livssituation med många svårigheter liknande andra anhörigvårdare med sjukdomstillstånd som parkinsons sjukdom och alzheimers sjukdom. Det är därför viktigt för sjuksköterskan att att få en förståelse för vad anhörigvårdare går igenom vid vårdandet av en individ med HS för att kunna förstå och ge adekvat stöd. Syftet: med litteraturstudien är att beskriva anhörigas perspektiv av att vara vårdare för en anhörig som är drabbad av huntingtons sjukdom. Metod: för att analysera datan så användes en integrerad analysmetod enligt Whittemore & Knafl (2005). 12 inkluderades (2 kvantitativa, 10 kvalitativa) som samlades från två databaser. Resultat: analysen resulterade i fyra kategorier: Existera i rollen anhörigvårdare, hantera att vara anhörigvårdare, undvikande av sjukdomen, kämpa för att få stöd och förståelse. Resultatet påvisade bland annat hur anhörigvårdares liv förändras samt hur det kan se ut när anhörigvårdare hanterar den nya situationen. Det är viktigt för sjukvården att ha insikt för vad anhörigvårdare går igenom för att kunna ge ett adekvat stöd och bemötande.