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Huntington disease (HD) is a degenerative neurological disease that typically onsets in midlife. It leads to progressively severe impairment in cognitive, behavioral, and motor function and premature death. Persons who test positive for the HD gene expansion know they will develop the disease. Research indicates changes are detectable several years before onset. Thus, HD has a long prodromal period (prHD). While researchers are aware of changes, little is known whether persons with prHD or their companions notice changes, or how they make sense of and cope with them. Leventhal and colleagues developed the Common Sense Model of Illness Representation (CSM) to describe how people make sense of illness. According to the CSM, people notice somatic changes, form illness representations, select coping procedures and evaluate them, and reappraise illness representations in an iterative process. The CSM has been used to explore illness representations in a variety of illnesses, including diagnosed HD. The authors of the model state it is also applicable in anticipated illness but this assertion has not been adequately tested. The purpose of this thesis was to use the CSM to explore and describe illness representations in persons with prHD and their companions. The results of this exploration are presented in three papers. The first paper, presented in Chapter 2, was a preliminary study based on interview data from 8 persons and 7 companions. Results of this analysis indicated persons with prHD and companions noticed and made attributions for changes, suggesting they formed illness representations. However, they were unsure whether some changes were related to HD. Results were considered preliminary because participants were not directly asked to make attributions. Data were also limited to changes in work function and the sample size was small. In the next two papers, 23 couples were interviewed. The purpose of the second paper, presented in Chapter 3, was to explore illness representations in persons with prHD and their companions and evaluate the usefulness of the CSM in anticipated illness using prHD as a model. Results supported preliminary findings: Participants noticed changes, made attributions, used coping strategies and evaluated them. Again, they unsure whether some changes were related to HD. Other elements of the CSM were partially supported by the data. The third paper, presented in Chapter 4, used quantitative and qualitative methods to explore coping in persons with prHD and companions. Participants were asked open-ended questions about how they coped with changes and were also verbally administered the Brief COPE scale. Both quantitative and qualitative data showed participants used active coping, acceptance, planning, and social support. Participants rarely used denial or substance abuse. Persons with prHD used more coping strategies than companions. Three major themes from the qualitative interview were identified: trying to fix it, can't fix it, and not broken yet. Qualitative interviews revealed some coping strategies that the Brief COPE did not measure. Findings from these papers may inform interventions to help people with prHD and companions cope with changes. Persons with prHD and companions might benefit from knowing what changes might be related to HD in order to cope more effectively.

In neurons, modification by the lipid palmitate regulates trafficking and function of signaling molecules, neurotransmitter receptors and associated synaptic scaffolding proteins. HIP14 (huntingtin interacting protein 14) is the first identified and characterized mammalian palmitoyl transferase that regulates this process. I have shown that HIP14 has striking effects on modulating trafficking and function of many proteins important for synapse formation and plasticity such as PSD-95, a postsynaptic scaffolding molecule. The importance of the finding that HIP14 is a neuronal palmitoyl transferase is further emphasized by our recent discovery that huntingtin protein folding, trafficking and function are regulated by the enzyme HIP14. Expansion of the polyglutamine tract in huntingtin as seen in Huntington Disease (HD) results in reduced association with HIP14 and decreased palmitoylation of huntingtin, which contributes to the formation of inclusion bodies and enhanced neuronal toxicity. By manipulating HIP14 levels through expression or knockdown, we can manipulate the number of huntingtin inclusion bodies and neuronal cell viability. Overall, these discoveries offer novel mechanism for HD pathogenesis and provide new approaches to therapy for HD. The tight association of HIP14 with wild-type huntingtin, which differs from other known enzyme-substrate interactions, indicates that huntingtin serves other functions beyond being a substrate of HIP14. I have discovered that, in vitro, wild-type huntingtin may facilitate activity of HIP14 to palmitoylate other neuronal substrates such as SNAP25, PSD95 and GAD65. By contrast, mutant htt does not act this way, probably due to lack of interaction with HIP14. Furthermore, immunoprecipitated HIP14 from huntingtin+/- mice also exhibits less enzyme activity in palmitoylating GST-SNAP25 in vitro, suggesting that decreased huntingtin expression compromises HIP14 activity. In vivo, using Acyl Biotin Exchange assay, I have also found that palmitoylation of a number of presynaptic and postsynaptic proteins that are involved in neurotransmission are reduced in huntingtin+/- mice. This study not only ascribes an important biochemical function to wild-type huntingtin, but also suggests that defects in protein palmitoylation in general due to mutant huntingtin lack of ability to facilitate HIP14 activity may contribute to the pathogenesis of HD.

In neurons, modification by the lipid palmitate regulates trafficking and function of signaling molecules, neurotransmitter receptors and associated synaptic scaffolding proteins. HIP14 (huntingtin interacting protein 14) is the first identified and characterized mammalian palmitoyl transferase that regulates this process. I have shown that HIP14 has striking effects on modulating trafficking and function of many proteins important for synapse formation and plasticity such as PSD-95, a postsynaptic scaffolding molecule. The importance of the finding that HIP14 is a neuronal palmitoyl transferase is further emphasized by our recent discovery that huntingtin protein folding, trafficking and function are regulated by the enzyme HIP14. Expansion of the polyglutamine tract in huntingtin as seen in Huntington Disease (HD) results in reduced association with HIP14 and decreased palmitoylation of huntingtin, which contributes to the formation of inclusion bodies and enhanced neuronal toxicity. By manipulating HIP14 levels through expression or knockdown, we can manipulate the number of huntingtin inclusion bodies and neuronal cell viability. Overall, these discoveries offer novel mechanism for HD pathogenesis and provide new approaches to therapy for HD. The tight association of HIP14 with wild-type huntingtin, which differs from other known enzyme-substrate interactions, indicates that huntingtin serves other functions beyond being a substrate of HIP14. I have discovered that, in vitro, wild-type huntingtin may facilitate activity of HIP14 to palmitoylate other neuronal substrates such as SNAP25, PSD95 and GAD65. By contrast, mutant htt does not act this way, probably due to lack of interaction with HIP14. Furthermore, immunoprecipitated HIP14 from huntingtin+/- mice also exhibits less enzyme activity in palmitoylating GST-SNAP25 in vitro, suggesting that decreased huntingtin expression compromises HIP14 activity. In vivo, using Acyl Biotin Exchange assay, I have also found that palmitoylation of a number of presynaptic and postsynaptic proteins that are involved in neurotransmission are reduced in huntingtin+/- mice. This study not only ascribes an important biochemical function to wild-type huntingtin, but also suggests that defects in protein palmitoylation in general due to mutant huntingtin lack of ability to facilitate HIP14 activity may contribute to the pathogenesis of HD.

In neurons, modification by the lipid palmitate regulates trafficking and function of signaling molecules, neurotransmitter receptors and associated synaptic scaffolding proteins. HIP14 (huntingtin interacting protein 14) is the first identified and characterized mammalian palmitoyl transferase that regulates this process. I have shown that HIP14 has striking effects on modulating trafficking and function of many proteins important for synapse formation and plasticity such as PSD-95, a postsynaptic scaffolding molecule. The importance of the finding that HIP14 is a neuronal palmitoyl transferase is further emphasized by our recent discovery that huntingtin protein folding, trafficking and function are regulated by the enzyme HIP14. Expansion of the polyglutamine tract in huntingtin as seen in Huntington Disease (HD) results in reduced association with HIP14 and decreased palmitoylation of huntingtin, which contributes to the formation of inclusion bodies and enhanced neuronal toxicity. By manipulating HIP14 levels through expression or knockdown, we can manipulate the number of huntingtin inclusion bodies and neuronal cell viability. Overall, these discoveries offer novel mechanism for HD pathogenesis and provide new approaches to therapy for HD. The tight association of HIP14 with wild-type huntingtin, which differs from other known enzyme-substrate interactions, indicates that huntingtin serves other functions beyond being a substrate of HIP14. I have discovered that, in vitro, wild-type huntingtin may facilitate activity of HIP14 to palmitoylate other neuronal substrates such as SNAP25, PSD95 and GAD65. By contrast, mutant htt does not act this way, probably due to lack of interaction with HIP14. Furthermore, immunoprecipitated HIP14 from huntingtin+/- mice also exhibits less enzyme activity in palmitoylating GST-SNAP25 in vitro, suggesting that decreased huntingtin expression compromises HIP14 activity. In vivo, using Acyl Biotin Exchange assay, I have also found that palmitoylation of a number of presynaptic and postsynaptic proteins that are involved in neurotransmission are reduced in huntingtin+/- mice. This study not only ascribes an important biochemical function to wild-type huntingtin, but also suggests that defects in protein palmitoylation in general due to mutant huntingtin lack of ability to facilitate HIP14 activity may contribute to the pathogenesis of HD. / Medicine, Faculty of / Graduate

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

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a mutation involving an expansion of the CAG trinucleotide repeats in the gene encoding for huntingtin (HTT) protein. The discovery of the disease-causing faulty gene (mutant huntingtin; mHTT) has enabled valid presymptomatic gene assessment for HD with results being categorized as ‘gene-expanded (GE; CAG repeats ≥ 36)' or ‘gene non-expanded (GNE)'. Individuals tested to be gene-expanded are destined to develop HD symptoms and will receive clinical diagnosis at an average age of 40 years when abnormal motor symptoms manifest. Those who are GNE will not develop HD. The availability of genetic testing has also provided a valuable research opportunity to study the pathoetiology of HD in PreHD subjects (those tested to be ‘gene-expanded' but are in the prediagnostic stage of HD). The genetic mutation results in widespread neuronal degeneration preferentially within the striatum. The clinical manifestations of HD include a triad of motor, cognitive and psychiatric symptoms. Challenging the classical view of HD as a neurodegenerative disease, recent studies have brought about a conceptual shift to include abnormal neurodevelopmental aspects in the etiology of HD1, based on the notion that lifelong HTT gene mutation may compromise HTT's crucial role in normal brain development. The fronto-striatal circuitry has been a main interest in HD research for its profound pathological association with symptom manifestation and marked neuroanatomical change. However, no study to date has investigated the neuropathological alteration of the fronto-striatal circuitry during childhood in mHTT carriers. In line with the proposed new perspective, the overall hypothesis of the current proposal is that the deteriorating effect of mHTT on the fronto-striatal circuits stems from abnormal development of these circuits. Therefore, the main goal of the current study was to enhance our understanding of how mHTT alters the evolving capacity of the fronto-striatal circuitry from a developmental perspective. To this end, the study examined the fronto-striatal circuit structure (using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI)) and function (using resting state functional MRI and cognitive/behavior tests) in children (6-18 years of age) at risk for HD. Healthy control children with no family history of HD were also evaluated. For research purposes only, children at risk for HD were genotyped and designated as GE or GNE based the result of their genetic testing. While the assessment of the fronto-striatal circuit development focused on anatomical delineations, the tests of the fronto-striatal circuit functionality were carried out separately for the three distinct cognitive, motor and affective loops within the fronto-striatal circuitry. The overall aim of the project was to evaluate the effect of mHTT on subcortical brain structures, white matter connection development and functional integrity of the cognitive, motor and affective loops within the fronto-striatal circuitry in Gene-Expanded (GE) children compared to those of Healthy Control (HC) children and again to those who are Gene Non-Expanded (GNE). Test of the hypothesized mHTT-associated developmental alteration of the fronto-striatal circuitry was addressed in two specific aims: Specific Aim #1: To observe subcortical gray matter volumes and white matter integrity of the fronto-striatal circuitry in children at risk for HD Decline in corpus striatal volume as well as aberrant fronto-striatal circuit connectivity has been reported in manifest HD patients and also in preHD adults.2-4 However, there is no experimental evidence of the onset or pattern of the pathophysiological change in the fronto-striatal circuitry. Therefore, volumes of subcortical structures and white matter integrity were measured in order to assess the development of the fronto-striatal circuitry in children at risk for HD. Specific Aim #2: To assess the functionalities of specific fronto-striatal circuit loops in children at risk for HD Functional abnormalities of the fronto-striatal circuitry have been observed in HD patients as well as in preHD adults.5 In order to closely examine the mHTT effect on fronto-striatal circuit function, resting state functional connectivity as well as performances on cognitive and behavioral tasks tapping into the functionality of the three fronto-striatal loops were evaluated in children at risk for HD. It was hypothesized that GE children would have diminished fronto-striatal circuit function. The GE children were predicted to show statistically significant deficits in 1) resting state functional connectivity between specific frontal lobe areas and striatal sub-regions, 2) cognitive control, 3) motoric control and 4) behavior control when compared to healthy controls and children without the HTT CAG expansion. The current study reports the baseline profile of the fronto-striatal structure and function in children at risk for HD. We have found that children who are on average 30 years ahead of HD diagnosis to have developmental alterations in the brain structure and function directly linked to the effect of mHTT. Brain morphology analysis revealed specific subcortical gray and white matter changes. The changes include disproportionately smaller caudate and putamen volumes and increased radial diffusivity localized to the external capsule which were more evident in males with HTT gene expansion. Fronto-striatal circuit functional assessment revealed a drop in motor functionality (both at rest and active performance) and externalizing behavior problems indicative of compromised inhibition than aggression. Children from HD families but do not have the genetic mutation also showed development aberrations in both brain structure and function when compared to healthy controls. Importantly, the altered structural morphology and functional profile seen in the GNE group differed from that of the GE children, emphasizing the impact of mHTT. The findings from those who share similar household environment but differ in genetic expansion status are important in highlighting the potential interaction of gene-environment effect on the manifestation of mHTT related changes seen in the children with the genetic expansion for HD. Investigation of subtle but persistent effects of mHTT on normal neural developmental processes may further our understanding of the pathogenesis of HD. Continuous longitudinal comprehensive assessments of the mHTT associated neurophenotype would aid in prognostic scenario estimation and thereby lead to effective clinical decision making to maximize the benefit of early intervention.

Introduktion: Huntingtons sjukdom (HS) är en neurologisk sjukdom som är ärftlig. Sjukdomen påverkar hjärnans nervceller och ger symtom som ofrivilliga ryckningar i extremiteterna. Sväljsvårigheter och problem att formulera meningar är också något som medföljer sjukdomen. I ett senare stadie av sjukdomen är personen helt beroende av att få hjälp med vardagliga sysslor som att kliva upp, gå på toaletten och duscha. Anhöriga blir ofta vårdare åt den sjuka.  Syfte: Syftet med studien var att beskriva erfarenheter hos närstående till personer med HS, samt att beskriva undersökningsgrupperna ur de valda artiklarna som använts i föreliggande studie.  Metod: Studien är en beskrivande litteraturstudie som är baserad på 11 vetenskapliga artiklar. Databaserna som använts för att hitta artiklar är PubMed och Cinahl.  Resultat: Partners till personer med HS anpassade sej till de nya förhållandena och övervägde ganska snabbt om de ville bli vårdare eller om de ville skiljas. Barn till föräldrar med HS hade inget val och fick ta mycket vuxenansvar i hemmet. Med sjukdomens progress blev vårdandet tyngre och närstående lade sitt eget liv ”på vänt”. Oron för framtiden hanterades genom att förneka eller att förbereda sej. Förståelse och hjälp fick närstående från andra i liknande situation. Sjukvården idag visste lite om sjukdomen och närståendes behov vilket skadade förtroendet. Slutsats: Närstående och anhörigvårdare upplevde en stor förändring i livet när sjukdomen blev värre. De kände oro och stress inför framtiden och deras relation till den sjuke förändrades med tiden. De möttes ofta av okunskap om sjukdomen. Anpassad information och stöttning längs vägen var något närstående önskade, men sällan fick uppleva. All tid och alla känslor gick åt att ta hand om och oroa sej för den sjuke. Rädslan för att gemensamma barn bar på genen var ständigt återkommande. / Introduction: Huntington’s disease (HD) is a genetic neurological disease. It affects the brains nerve cells. Symptoms include involuntary spasms, inability to swallow and difficulty putting together sentences. In the latter stages of the disease patients become completely dependent on help with everyday chores like getting out of bed, using the bathroom and showering. It’s very common for close family and relatives to become carers to the patients. Purpose: The aim of the study was to research the effects HD has on immediate family and carers of an HD patient, furthermore to describe the included scientific articles study group. Method: The study is a descriptive literature study based on 11 scientific articles. The databases used for research are: PubMed and Cinahl Results: Related parties that were partners to people with HD adapted themselves to the new conditions and considered, fairly quickly if they wanted to become a caregiver or if they wanted a divorce. Children of parents with HD had no choice and had to take a lot of adult responsibilities at home. With the progression of the disease, caring became heavier and relatives put their own lives "on hold". Concerns for the future were handled by denying or preparing. Understanding and the support was received from people in similar situations. Healthcare today know little about the disease and related parties' needs, which damaged confidence. Conclusion: Related parties and family caregivers experienced a big change in life when the disease got worse. They worried and were stressed about the future and their relationship to the patient changed with time. They often met ignorance about the disease. Adapted information and support along the way was something related parties desired, but rarely experienced. All time and emotions were spent, taking care of and worry about the sick. The fear of the children carrying the gene were constantly recurring.

La maladie de Huntington (MH) est une maladie neurodégénérative héréditaire autosomique dominante. Elle est due à l’expansion anormale de polyglutamine dans la partie N-terminal de la protéine huntingtine (HTT). Une des étapes clés de la pathologie est le clivage de la HTT pleine longueur en fragments N-terminaux plus petits, contenant l’expansion de polyglutamine, et qui sont toxiques pour les neurones. En effet, les clivages de la HTT mutée génère des fragments N-terminaux (N-ter) de tailles comprises entre les acides aminés 1-105 et 1-586 observés dans des extraits de cerveaux de patients MH post-mortem et dont l’implication dans la mort neuronal est bien caractérisée. Mes travaux de thèse ont visé à modéliser le clivage de la HTT et à évaluer les conséquences sur la survie neuronale.Au cours de ma thèse, j’ai développé un outil permettant de contrôler le clivage de la HTT dans le temps et à des sites spécifiques. J’ai étudié le clivage de la HTT à deux sites stratégiques : les positions clivées par la caspase-6 et par la bléomycine hydrolase/cathepsine Z. A l’aide de cet outil, j’ai montré que le clivage de la HTT confère une toxicité cellulaire qui dépend du profil du clivage. Plus précisément, J’ai décrit une interaction intramoléculaire au sein des domaines de la HTT. Mes résultats indiquent que cette interaction protège les cellules de la toxicité induite par le clivage de la HTT mutée. En effet, les clivages successifs de la HTT annulent cette interaction, ce qui induit la libération des fragments N-ter mutants et provoque la mort cellulaire à l’issue de leur translocation nucléaire. Pour conclure, au cours de ma thèse, j’ai montré que la protéolyse successive de la HTT induit des processus cytotoxiques différents. / Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in the N-terminus of the protein huntingtin (HTT). A crucial step in HD pathogenesis is the cleavage of full-length HTT into smaller N-terminal (N-ter) fragments that contain the polyQ stretch and that are toxic to neurons. HTT cleavage generates short N-ter fragments whose amino-acid positions range from 1-105 to 1-586. These fragments are observed in HD post mortem brain samples and their participation in neuronal death in HD is well characterized. During my PhD research, I investigated the consequences of full-length mutant HTT proteolysis by developing a time and site-specific controlled system for HTT proteolysis. I have assessed HTT cleavage on two sites caspase-6 and cathepsin Z. My results show that HTT cleavage induces neurotoxicity in vitro as well as in vivo, toxicity which depends on HTT proteolysis pattern. Briefly, we described an intramolecular interaction within the HTT domains which is impaired upon successive proteolysis of HTT. We found that HTT intramolecular interaction buffer mutant N-ter HTT-induced toxicity. Moreover, specific cleavages of the mutant HTT generated toxic N-ter fragments as they translocate into the nucleus. To conclude, my PhD work has shown that additional cleavage of mutant HTT induces cytotoxicity by different mechanisms.

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