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.

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.

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.

Yes / Topoisomerase1 (TOP1)-mediated chromosomal breaks are endogenous sources of DNA damage that affect neuronal genome stability. Whether TOP1 DNA breaks are sources of genomic instability in Huntington's disease (HD) is unknown. Here, we report defective 53BP1 recruitment in multiple HD cell models, including striatal neurons derived from HD patients. Defective 53BP1 recruitment is due to reduced H2A ubiquitination caused by the limited RNF168 activity. The reduced availability of RNF168 is caused by an increased interaction with p62, a protein involved in selective autophagy. Depletion of p62 or disruption of the interaction between RNAF168 and p62 was sufficient to restore 53BP1 enrichment and subsequent DNA repair in HD models, providing new opportunities for therapeutic interventions. These findings are reminiscent to what was described for p62 accumulation caused by C9orf72 expansion in ALS/FTD and suggest a common mechanism by which protein aggregation perturb DNA repair signaling. / This work is funded by a Welcome Trust Investigator Award (103844), a Lister Institute of Preventative Medicine Fellowship (137661) and a UKIERI grant (DST/INT/UK/P-147/2016) to S.F.E.- K. JG is additionally funded by a Clinical PhD Fellowship from the Pathological Society of Great Britain and Ireland and the Jean Shanks Foundation (JSPS-CPHD-2018-01).

Located on the short arm of chromosome 4, there exists a gene, IT15, responsible for the trinucleotide CAG expansion involved in the autosomal dominant neurodegenerative disorder known as Huntington’s disease (HD). The brain region associated with the most atrophy, the striatum, leads to expression of severe motor dysfunction, the hallmark feature of HD. To a lesser degree, the cortex and hippocampus show earlier deterioration indicative of the cognitive deficits that occur prior to motor symptom onset. The brain regions associated with HD-induced neuronal death additionally selectively express the protein Rhes - the combination of Rhes and mutant huntingtin being cytotoxic. Using a 3-nitropropionic acid animal model of HD, we hypothesized that animals with preserved prenylation of Rhes would display cognitive and motor symptomology similar to genetic models of HD while animals administered statins or bisphosphonates would show inhibited Rhes prenylation and delayed cognitive symptoms. Experimental animals, however, did not perform differently than control animals on shallow water variants of the t-maze and MWM.

La maladie de Huntington (HD) est une maladie génétique neurodégénérative qui touche environ 6000 personnes en France. Les manifestations psychiatriques sont une des composantes majeures des symptômes précoces de la pathologie. Ainsi, des épisodes dépressifs parfois associés à de l’anxiété généralisée sont communément observés au cours des stades pré-symptomatiques de la maladie. On connaît mal à l’heure actuelle les raisons de cette prévalence élevée. L'allèle responsable de la maladie code une protéine appelée huntingtine (HTT) dont l'expansion polyglutaminique (polyQ) en N-terminal est plus longue que dans la HTT non pathogénique. La huntingtine est impliquée dans diverses fonctions cellulaires et notamment dans le transport et l’expression d’un facteur neurotrophique, le Brain-Derived Neurotrophic Factor (BDNF). Celui-ci est d’ailleurs connu pour son rôle dans la régulation des troubles de l’humeur, de la neurogénèse hippocampique chez l’adulte, ainsi que dans la réponse thérapeutique aux antidépresseurs. Nous avons émis l'hypothèse que la huntingtine, en plus de ses rôles connus dans le cortex et le striatum, puisse jouer également un rôle dans l'hippocampe. Ainsi, une altération du transport de BDNF dans l’hippocampe pourrait en partie expliquer les troubles de l’humeur observés chez les patients HD.Par une approche in vivo, en utilisant différents modèles de souris, nous avons ainsi démontré que la huntingtine stimule le trafic vésiculaire et la sécrétion de BDNF dans les neurones hippocampiques et que cette action peut être modulée par la mutation polyQ ou par le statut de phosphorylation de la protéine sur les sérines 1181 et 1201. Cela aboutit à des modifications des voies de signalisation (Akt, ERK, CREB) activées par le BDNF. Nous mettons également en évidence que la huntingtine sauvage est impliquée dans le soutien exercé par les neurones matures sur les nouveaux neurones, nécessaire à leur survie à long terme et à la formation d’une arborisation dendritique complexe. Le BDNF est l’intermédiaire idéal grâce à ses effets sur la neurogenèse hippocampique. Enfin, la huntingtine sauvage et ses formes mutées (polyQ et phosphorylation sur les sérines 1181 et 1201) sont impliquées dans le comportement anxio-dépressif des souris. / Huntington disease (HD) is a genetic neurodegenerative disorder that affects about 6,000 people in France. Psychiatric manifestations are an important component of the early symptoms of the disease. Indeed, depressive episodes sometimes associated with generalized anxiety are commonly observed during the pre-symptomatic stages of disease. Few information is available about the reasons for this high prevalence.The allele responsible for the disease encodes a protein called huntingtin (HTT) whose polyglutamine expansion (polyQ) in the N-terminal region is longer than in the non-pathogenic HTT. Huntingtin is involved in various cellular functions including the transport and the expression of a neurotrophic factor, the Brain-Derived Neurotrophic Factor (BDNF). This factor is also known for its role in the regulation of mood, adult hippocampal neurogenesis, and in the therapeutic response to antidepressants.We hypothesized that huntingtin, in addition to its known roles in the cortex and striatum, may play a role in the hippocampus. Thus, an impaired transport of BDNF in the hippocampus could partly explain the mood disorders observed in HD patients.By an in vivo approach using different mouse models, we demonstrated that huntingtin stimulates vesicular trafficking and secretion of BDNF in hippocampal neurons and that this action may be modulated by the polyQ mutation or by the phosphorylation status of the protein on serines 1181 and 1201. These lead to changes in signaling pathways (Akt, ERK, CREB) activated by BDNF.We also demonstrate that normal huntingtin is involved in the support provided by mature neurons to new neurons for their long-term survival and the formation of a complex dendritic arborization. BDNF is the ideal candidate to mediate these effects on hippocampal neurogenesis. Finally, normal huntingtin and its mutated forms (polyQ and phosphorylated on serines 1181 and 1201) are involved in anxiety and depressive-like phenotype in mice.