Indiana University-Purdue University Indianapolis (IUPUI) / Huntington disease (HD) is an autosomal dominant disorder characterized by progressive decline of motor, cognitive, and behavioral function. Saccades (rapid, gaze-shifting eye movements) are affected before a clinical diagnosis of HD is certain (i.e. during the premanifest period of the disease). Fundamental questions remain regarding the neural substrates of abnormal saccades and the course of premanifest disease. This work addressed these questions using magnetic resonance imaging (MRI) and a longitudinal study of premanifest disease progression. Gray matter atrophy is a characteristic of HD that can be reliably detected during the premanifest period, but it is not known how such changes influence saccadic behavior. We evaluated antisaccades (AS) and memory guided saccades (MG) in premanifest and manifest HD, then tested for associations between impaired saccadic measures and gray matter atrophy in brain regions involved in these saccadic tasks. The results suggest that slowed vertical AS responses indicate cortical and subcortical atrophy and may be a noninvasive marker of atrophic changes in the brain. We also investigated the brain changes that underlie AS impairment using an event-related AS design with functional MRI (fMRI). We found that, in premanifest and manifest HD, blood oxygenation level dependent (BOLD) response was abnormally absent in the pre-supplementary motor area and dorsal anterior cingulate cortex following incorrect AS responses. These results are the first to suggest that abnormalities in an error-related response network underlie early disease-related saccadic changes, and they emphasize the important influence of regions outside the striatum and frontal cortex in disease manifestations. Though saccadic abnormalities have been repeatedly observed cross sectionally, they have not yet been studied longitudinally in premanifest HD. We found different patterns of decline; for some measures the rate of decline increased as individuals approached onset, while for others the rate was constant throughout the premanifest period. These results establish the effectiveness of saccadic measures in tracking premanifest disease progression, and argue for their use in clinical trials. Together, these studies establish the utility of saccade measures as a marker of HD neurodegeneration and suggest that they would be a valuable component of batteries evaluating the efficacy of neuroprotective therapies.

Le contrôle postural et la perception des limites de la stabilité sont des processus complexes qui nécessitent le traitement et l’intégration d’informations sensorielles multimodales. Pendant l’enfance, le développement de la stabilité posturale s’effectue de façon non-monotonique. Plusieurs auteurs ont suggéré que ce profil non linéaire serait provoqué par une période de recalibration des systèmes sensoriels. Cette phase, nommée période de transition, est observée vers l’âge de 6-7 ans. Nous disposons toutefois de très peu d’information sur le rôle spécifique des afférences et des mécanismes d’intégration sensorielle au cours du développement postural. Les dysfonctions dans les noyaux gris centraux, telles que ceux observés dans la maladie de Parkinson, ont été associées à divers déficits dans le contrôle de la posture, dans le traitement et l’intégration sensoriel plus particulièrement, au niveau des informations proprioceptives. De plus, les limites fonctionnelles de la stabilité posturale des personnes atteintes de la maladie de Parkinson sont significativement réduites. Cependant, les connaissances concernant comment certaines pathologies des noyaux gris centraux, telles que le syndrome Gilles de la Tourette (SGT) et la maladie de Huntington (MH) affectent la capacité d’utiliser les informations sensorielles pour contrôler la posture demeurent à ce jour, incomplètes. Cette thèse porte sur le rôle des noyaux gris centraux dans les processus de traitements et d’intégration sensorielle, particulièrement les afférences proprioceptives dans le contrôle de la posture au cours du développement de l’enfant en santé, atteint du SGT et chez l’adulte atteint de la MH avec et sans symptôme clinique. Notre protocole expérimental a été testé chez ces trois populations (enfants en santé, SGT et MH). Nous avons utilisé des mesures quantitatives à partir de données issues d’une plateforme de force afin d’évaluer les ajustements posturaux dans les limites de la stabilité posturale. Les participants devaient s’incliner le plus loin possible dans quatre différentes directions (avant, arrière, droite et gauche) et maintenir l’inclinaison posturale maximale pendant 10 secondes. Afin de tester la capacité à traiter et à intégrer les informations sensorielles, la tâche expérimentale a été exécutée dans trois conditions sensorielles : 1) yeux ouverts, 2) yeux fermés et 3) yeux fermés, debout sur une mousse. Ainsi, la contribution relative de la proprioception pour le contrôle postural augmente à travers les conditions sensorielles. Dans la première étude, nous avons évalué la capacité à traiter et à intégrer les informations sensorielles avant (4 ans) et après (8-10 ans) la période de transition comparativement aux adultes. Dans la deuxième et la troisième étude, nous avons également évalué le traitement et l’intégration des informations sensorielles chez les patients atteints de désordres des noyaux gris centraux. La deuxième étude portera spécifiquement sur les adolescents atteints du SGT et la troisième, sur la MH avant et après l’apparition des symptômes cliniques. En somme, les résultats de la première étude ont démontré que la performance des enfants est affectée de façon similaire par les différentes conditions sensorielles avant et après la période de transition. Toutefois, le profil de développement des mécanismes responsables des ajustements posturaux de l’axe antéropostérieur est plus précoce comparativement à ceux de l’axe médiolatéral. Ainsi, nos résultats ne supportent pas l’hypothèse de la période de recalibration des systèmes sensoriels pendant cette période ontogénétique mais suggèrent que la période de transition peut être expliquée par la maturation précoce des mécanismes d’ajustements posturaux dans l’axe antéropostérieur. Dans l’ensemble, les résultats de nos études chez les populations atteintes de désordres des noyaux gris centraux (MH et SGT) démontrent non seulement qu’ils ont des déficits posturaux mais également que les ajustements posturaux dans les deux axes sont affectés par les conditions sensorielles. Pour la première fois, nos études démontrent des déficits globaux de traitements et d’intégration sensorielle accentués pour les signaux proprioceptifs. Ces résultats sont similaires à ceux observés dans la maladie de Parkinson. De plus, les adolescents atteints du SGT éprouvent également des troubles posturaux marqués dans la condition visuelle ce qui suggère des déficits d’intégrations visuelles et/ou multimodaux. / Postural control and the perception of the stability limits are complex mechanisms requiring the processing and integration of multimodal sensory information. During childhood, the development of postural control skills improves in a non-monotonic manner. Many researchers suggested that this non linear profile is caused by the recalibration of sensory systems. This recalibration phase, named transition period, is generally observed at 6-7 years of age. However, the exact cause of this critical turning point remains undetermined. Moreover, very little is known about the specific role of sensory information and sensorimotor mechanisms during postural development. Basal ganglia disorders such as Parkinson’s disease are associated with postural control impairments and deficits in the processing and integration of sensory information, especially in proprioception. Moreover, the limits of stability are significantly reduced in Parkinson’s disease. However, the knowledge on how other basal ganglia dysfunctions such as Gilles de la Tourette syndrome (GTS) and Huntington’s disease (HD) impact on the ability to process and integrate sensory information for postural control is still limited. In this thesis, we explored the role of basal ganglia in the processing an integration of sensory information, particularly proprioceptive signals for the postural control during the development of healthy children, in adolescents with GTS and in adults with premanifest and manifest HD. Our stability limits protocol was used to test the postural control skills of these three populations. We calculated center of pressure displacements obtained from a force plate and we investigated postural adjustments during the maximum leaning posture. The participants were asked to lean as far as possible and maintain this position during 10 seconds in different directions (forward, backward, rightward or leftward). This task simulates functional positions that frequently occur in daily life. In order to test the ability to process and integrate sensory information for postural control, the stability limits task was assessed in three sensory conditions: 1) eyes open, 2) eyes closed and 3) eyes closed while standing on foam. Thus, the relative contribution of proprioceptive signals for postural control increased across sensory conditions. In the first study, we investigated the children’s ability to process and integrate sensory information for postural control before (4 years old) and after (8 to 10 years old) the transition period compared to adults. In the second and third studies, the ability to process and integrate sensory information for postural control was assessed in participants with basal ganglia disorders, namely adolescents with GTS and adults with manifest and premanifest HD. In sum, our ontogenetic study indicated that the younger children (4 years old) were not differentially affected by sensory conditions than the older children (8 to 10 years old). Thus, our results do not support the hypothesis that an important recalibration of sensorial systems takes place during the transition period. However, the results revealed axis-dependent differences among the groups in postural control. Until the age of 10, children have a reduced ability to perform appropriate center of pressure adjustments along the mediolateral direction compared to adults. In contrast, the ability to produce precise center of pressure adjustments along the anteroposterior axis was already developed at 4 years of age, but it reached the adult level of performance after the transition period. Altogether, the assessment of participants with basal ganglia disorders indicated that they have postural adjustment impairments in both movement axes and are affected by sensory conditions. For the first time, we reported global deficits in the processing and integration of sensory information, especially in proprioception in GTS and in premanifest and manifest HD. These results are similar to those reported for Parkinson’s disease patients. Moreover, the adolescents with GTS also displayed marked postural control abnormalities in the visual condition which might be explained by either deficit in the processing of visual information and/or in multimodal sensory integration mechanisms.

La maladie de Huntington s’accompagne de troubles des conduites sociales perturbant les relations interindividuelles. L'objectif de ce travail de thèse était de mieux comprendre ces troubles sociaux en examinant les habiletés en cognition sociale de personnes porteuses de la mutation ou atteintes de cette maladie neurogénétique. La cognition sociale comprend notamment la reconnaissance des émotions d’autrui, les connaissances sociales et la théorie de l’esprit, soit la capacité à attribuer aux autres des états mentaux affectifs (sentiments) ou cognitifs (intentions,croyances). Nous avons étudié la cognition sociale à la phase présymptomatique et symptomatique de la maladie de Huntington à l’aide de tests neuropsychologiques et de la neuroimagerie morphologique et fonctionnelle. Ce travail a été réalisé dans le cadre d’une collaboration entre le centre national de référence pour les maladies neurogénétiques de l'adulte du CHU d’Angers et la plate-forme d’imagerie médicale Cyceron de Caen. Ce travail visait à mieux comprendre les perturbations en cognition sociale accompagnant la maladie de Huntington, leur évolution et leurs bases neurobiologiques afin d’améliorer notre compréhension des troubles du comportement accompagnant cette maladie. Nous espérons ainsi pouvoir mieux contribuer au diagnostic, au pronostic et à la prise en charge des personnes concernées par cette maladie. / Huntington's disease is accompanied by disturbances insocial behavior that disrupt inter-individual relationships.The aim of this thesis was to better understand these social disorders by examining the social cognition skills of people with the mutation or the neurogenic disease. Social cognition includes the recognition of the emotions of others, social knowledge and the theory of the mind, namely the ability to attribute to others emotional (feelings) or cognitive (intentions, beliefs) mental states. We studied social cognition in the presymptomatic and symptomatic phase of Huntington's disease using neuropsychological tests and morphological and functional neuroimaging. This work was carried out within the framework of a collaboration between the national center of reference for the neurogenic diseases of adults of the CHU of Angers and the platform of medical imaging Cyceron of Caen. This work aimed to better understand the social cognition disruptions accompanying Huntington's disease, their evolution and their neurobiological basis in order to improve our understanding of behavioral disorders accompanying this disease. We hope to be able to better contribute to the diagnosis, prognosis and care of those affected by this disease.

Le contrôle postural et la perception des limites de la stabilité sont des processus complexes qui nécessitent le traitement et l’intégration d’informations sensorielles multimodales. Pendant l’enfance, le développement de la stabilité posturale s’effectue de façon non-monotonique. Plusieurs auteurs ont suggéré que ce profil non linéaire serait provoqué par une période de recalibration des systèmes sensoriels. Cette phase, nommée période de transition, est observée vers l’âge de 6-7 ans. Nous disposons toutefois de très peu d’information sur le rôle spécifique des afférences et des mécanismes d’intégration sensorielle au cours du développement postural. Les dysfonctions dans les noyaux gris centraux, telles que ceux observés dans la maladie de Parkinson, ont été associées à divers déficits dans le contrôle de la posture, dans le traitement et l’intégration sensoriel plus particulièrement, au niveau des informations proprioceptives. De plus, les limites fonctionnelles de la stabilité posturale des personnes atteintes de la maladie de Parkinson sont significativement réduites. Cependant, les connaissances concernant comment certaines pathologies des noyaux gris centraux, telles que le syndrome Gilles de la Tourette (SGT) et la maladie de Huntington (MH) affectent la capacité d’utiliser les informations sensorielles pour contrôler la posture demeurent à ce jour, incomplètes. Cette thèse porte sur le rôle des noyaux gris centraux dans les processus de traitements et d’intégration sensorielle, particulièrement les afférences proprioceptives dans le contrôle de la posture au cours du développement de l’enfant en santé, atteint du SGT et chez l’adulte atteint de la MH avec et sans symptôme clinique. Notre protocole expérimental a été testé chez ces trois populations (enfants en santé, SGT et MH). Nous avons utilisé des mesures quantitatives à partir de données issues d’une plateforme de force afin d’évaluer les ajustements posturaux dans les limites de la stabilité posturale. Les participants devaient s’incliner le plus loin possible dans quatre différentes directions (avant, arrière, droite et gauche) et maintenir l’inclinaison posturale maximale pendant 10 secondes. Afin de tester la capacité à traiter et à intégrer les informations sensorielles, la tâche expérimentale a été exécutée dans trois conditions sensorielles : 1) yeux ouverts, 2) yeux fermés et 3) yeux fermés, debout sur une mousse. Ainsi, la contribution relative de la proprioception pour le contrôle postural augmente à travers les conditions sensorielles. Dans la première étude, nous avons évalué la capacité à traiter et à intégrer les informations sensorielles avant (4 ans) et après (8-10 ans) la période de transition comparativement aux adultes. Dans la deuxième et la troisième étude, nous avons également évalué le traitement et l’intégration des informations sensorielles chez les patients atteints de désordres des noyaux gris centraux. La deuxième étude portera spécifiquement sur les adolescents atteints du SGT et la troisième, sur la MH avant et après l’apparition des symptômes cliniques. En somme, les résultats de la première étude ont démontré que la performance des enfants est affectée de façon similaire par les différentes conditions sensorielles avant et après la période de transition. Toutefois, le profil de développement des mécanismes responsables des ajustements posturaux de l’axe antéropostérieur est plus précoce comparativement à ceux de l’axe médiolatéral. Ainsi, nos résultats ne supportent pas l’hypothèse de la période de recalibration des systèmes sensoriels pendant cette période ontogénétique mais suggèrent que la période de transition peut être expliquée par la maturation précoce des mécanismes d’ajustements posturaux dans l’axe antéropostérieur. Dans l’ensemble, les résultats de nos études chez les populations atteintes de désordres des noyaux gris centraux (MH et SGT) démontrent non seulement qu’ils ont des déficits posturaux mais également que les ajustements posturaux dans les deux axes sont affectés par les conditions sensorielles. Pour la première fois, nos études démontrent des déficits globaux de traitements et d’intégration sensorielle accentués pour les signaux proprioceptifs. Ces résultats sont similaires à ceux observés dans la maladie de Parkinson. De plus, les adolescents atteints du SGT éprouvent également des troubles posturaux marqués dans la condition visuelle ce qui suggère des déficits d’intégrations visuelles et/ou multimodaux. / Postural control and the perception of the stability limits are complex mechanisms requiring the processing and integration of multimodal sensory information. During childhood, the development of postural control skills improves in a non-monotonic manner. Many researchers suggested that this non linear profile is caused by the recalibration of sensory systems. This recalibration phase, named transition period, is generally observed at 6-7 years of age. However, the exact cause of this critical turning point remains undetermined. Moreover, very little is known about the specific role of sensory information and sensorimotor mechanisms during postural development. Basal ganglia disorders such as Parkinson’s disease are associated with postural control impairments and deficits in the processing and integration of sensory information, especially in proprioception. Moreover, the limits of stability are significantly reduced in Parkinson’s disease. However, the knowledge on how other basal ganglia dysfunctions such as Gilles de la Tourette syndrome (GTS) and Huntington’s disease (HD) impact on the ability to process and integrate sensory information for postural control is still limited. In this thesis, we explored the role of basal ganglia in the processing an integration of sensory information, particularly proprioceptive signals for the postural control during the development of healthy children, in adolescents with GTS and in adults with premanifest and manifest HD. Our stability limits protocol was used to test the postural control skills of these three populations. We calculated center of pressure displacements obtained from a force plate and we investigated postural adjustments during the maximum leaning posture. The participants were asked to lean as far as possible and maintain this position during 10 seconds in different directions (forward, backward, rightward or leftward). This task simulates functional positions that frequently occur in daily life. In order to test the ability to process and integrate sensory information for postural control, the stability limits task was assessed in three sensory conditions: 1) eyes open, 2) eyes closed and 3) eyes closed while standing on foam. Thus, the relative contribution of proprioceptive signals for postural control increased across sensory conditions. In the first study, we investigated the children’s ability to process and integrate sensory information for postural control before (4 years old) and after (8 to 10 years old) the transition period compared to adults. In the second and third studies, the ability to process and integrate sensory information for postural control was assessed in participants with basal ganglia disorders, namely adolescents with GTS and adults with manifest and premanifest HD. In sum, our ontogenetic study indicated that the younger children (4 years old) were not differentially affected by sensory conditions than the older children (8 to 10 years old). Thus, our results do not support the hypothesis that an important recalibration of sensorial systems takes place during the transition period. However, the results revealed axis-dependent differences among the groups in postural control. Until the age of 10, children have a reduced ability to perform appropriate center of pressure adjustments along the mediolateral direction compared to adults. In contrast, the ability to produce precise center of pressure adjustments along the anteroposterior axis was already developed at 4 years of age, but it reached the adult level of performance after the transition period. Altogether, the assessment of participants with basal ganglia disorders indicated that they have postural adjustment impairments in both movement axes and are affected by sensory conditions. For the first time, we reported global deficits in the processing and integration of sensory information, especially in proprioception in GTS and in premanifest and manifest HD. These results are similar to those reported for Parkinson’s disease patients. Moreover, the adolescents with GTS also displayed marked postural control abnormalities in the visual condition which might be explained by either deficit in the processing of visual information and/or in multimodal sensory integration mechanisms.

Thesis (Ph. D.)--University of Lund, 1994. / Published dissertation. Includes bibliographical references.

Thesis (Ph. D.)--University of Lund, 1994. / Published dissertation. Includes bibliographical references.

The causative role of the huntingtin (HTT) gene in Huntington's disease (HD) has been identified more than 25 years ago. The extension of CAG repeat stretch over 39 repeats in exon 1 of one HTT allele results in full penetrance of this neurodegenerative disorder. While the identification of the causative mutation raised hopes that development of the therapeutic compound will be easily achievable, the patients and their families are still waiting for treatment until now. The main reason for that might be the complex cellular function HTT that makes the determination of the pathologic mechanism difficult and the development of treatments even more challenging. Although a lot of different animal models have been generated until now, establishing a suitable model has still not been achieved yet. Due to its anatomy, physiology, and genetics, the minipig seems to be a suitable candidate for neurodegenerative disease models. Indeed, the existing Transgenic (Tg) Libechov minipig model manifests signs typical for HD in patients, but on the other hand significant inconsistencies have also been observed. The finding of malformation that partially shows the situation in human patients is true for both, the male reproductive tract as well as for the brain. The reason for this might be the fact the genetic...

The causative role of the huntingtin (HTT) gene in Huntington's disease (HD) has been identified more than 25 years ago. The extension of CAG repeat stretch over 39 repeats in exon 1 of one HTT allele results in full penetrance of this neurodegenerative disorder. While the identification of the causative mutation raised hopes that development of the therapeutic compound will be easily achievable, the patients and their families are still waiting for treatment until now. The main reason for that might be the complex cellular function HTT that makes the determination of the pathologic mechanism difficult and the development of treatments even more challenging. Although a lot of different animal models have been generated until now, establishing a suitable model has still not been achieved yet. Due to its anatomy, physiology, and genetics, the minipig seems to be a suitable candidate for neurodegenerative disease models. Indeed, the existing Transgenic (Tg) Libechov minipig model manifests signs typical for HD in patients, but on the other hand significant inconsistencies have also been observed. The finding of malformation that partially shows the situation in human patients is true for both, the male reproductive tract as well as for the brain. The reason for this might be the fact the genetic...

Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a sizable economic cost. Adeno-associated viral (AAV) vectors have emerged as an effective platform for CNS gene therapy and have shown early promise in clinical trials. These trials involve direct infusion into brain parenchyma, an approach that may be suboptimal for treatment of neurodegenerative disorders, which often involve more than a single structure in the CNS. However, overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. We have developed novel capsids AAV-AS and AAV-B1 that lead to widespread gene delivery throughout the brain and spinal cord, particularly to neuronal populations. Both transduce the adult mouse brain >10-fold more efficiently than the clinical gold standard AAV9 upon intravascular infusion, with gene transfer to multiple neuronal sub-populations. These vectors are also capable of neuronal transduction in a normal cat. We have demonstrated the efficacy of AAV-AS in the context of Huntington's disease by knocking down huntingtin mRNA 33-50% after a single intravenous injection, which is better than what can be achieved by AAV9 at the particular dose. AAVB1 additionally transduces muscle, beta cells, pulmonary alveoli and retinal vasculature at high efficiency, and has reduced sensitivity to neutralizing antibodies in human sera. Generation of this vector toolbox represents a major step towards gaining genetic access to the entire CNS, and provides a platform to develop new gene therapies for neurodegenerative disorders.

Protein-Protein Interaktions (PPI) Netzwerke liefern ein Grundgerüst für systematische Untersuchungen der komplexen molekularen Maschinerie in der Zelle. Die Komplexität von Protein-Wechselwirkungen stellt jedoch in Bezug auf ihre Identifizierung, Validierung und Annotation eine große experimentelle und rechnerische Herausforderung dar. In dieser Arbeit analysierte ich diese Probleme und lieferte Lösungen, um die Limitierungen aktueller humanen PPI Netzwerke zu überwinden. Meine Arbeit kann in zwei Teile aufgeteilt werden: Im ersten Teil führte ich eine kritischen Vergleich von acht unabhängig konstruierten humanen PPI Netzwerke durch, um mögliche experimentellen Verzerrungen zu erkennen. Die Ergebnisse zeigten starke Tendenzen bezüglich der Selektion und Detektion von Interaktionen, die in zukünftigen Anwendungen dieser Netzwerke berücksichtigt werden sollten. Einer der wichtigsten Schlussfolgerungen dieser Studie war, dass die derzeitigen humanen Interaktions Netzwerke komplementär sind und deshalb wurde eine Datenbank mit der Bezeichnung Unified Human Interaktome (UniHI) entwickelt, die menschliche PPI Daten aus zwölf wichtigsten Quellen integriert. Im zweiten Teil dieser Forschungsarbeit benutzte ich die Daten aus der UniHI Datenbank, die genetischen Modifikatoren in einer bestimmten Krankheit, Chorea Huntington (HD) eine autosomal dominante neurodegenerative Erkrankung, zu charakterisieren. Um die Proteine zu identifizieren, die den Krankheitsverlauf modifizieren können, wurden Protein Interaktion Daten mit Genexpressionsdaten von HD-Patienten in Kombination mit einem Mehrschritt-Filterungsverfahren integriert. Mit dem neuartigen Ansatz wurde ein Nucleus caudatus-spezifische Protein-Interaktion HD (PPI)-Netzwerk vorhergesagt, das 14 potentiell dysregulierten Proteine direkt oder indirekt mit dem Huntingtin-Protein verlinkt, mit mögliche Verbindung zu Molekularen Prozessen wie z.B. Apoptose, Metabolismus, neuronale Entwicklung. / Protein interaction networks aim to provide the scaffold maps for systematic studies of the complex molecular machinery in the cell. The complexity of protein interactions poses, however, large experimental and computational challenges regarding their identification, validation and annotation. Additionally, storage and linking is demanding since new data are rapidly accumulating. In this research work, I addressed these issues and provided solutions to overcome the limitations of current human protein-protein interaction (PPI) maps. In particular, my thesis can be partitioned into two parts: In the first part, I conducted a comparative assessment of eight recently constructed human protein-protein interaction networks to identify experimental biases. Results showed strong selection and detection biases which are necessary to take into consideration in future applications of these maps. One of the important conclusions of this study was that the current human interaction networks contain complementary information; hence, a database was developed, termed as Unified Human Interactome (UniHI), integrating human PPI data from twelve major sources. Several new tools were included for querying, analyzing and visualizing human PPI networks. In the second part of this research work, UniHI dataset was applied to characterize the genetic modifiers involved in a specific disease: Chorea Huntington (HD), an autosomal dominant neurodegenerative disease. To find the modifiers, a network-based modeling approach was implemented by integrating huntingtin-specific protein interaction network with gene expression data from HD patients in multiple steps. Using this approach, a Caudate Nucleus-specific HD protein interaction (PPI) network was predicted, connecting 14 potentially dysregulated proteins directly or indirectly to the disease protein, showing a possible link to molecular processes such as pro-apoptotic pathways, cell survival, anti-apoptotic, growth, and neuronal diseases.