No description available.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.

Univ., Diss.--Lübeck, 2005.

Thesis (M.A.)--Brigham Young University. Dept. of English. / Includes bibliographical references.

Thèse (M.Sc.)--Université Laval, 2004. / Bibliogr.: f. 77-90. Publié aussi en version électronique.

- / -

Posttranslationale Modifikationen modulieren verschiedene Charakteristika von Proteinen. Sie können die Aktivität, Lokalisierung und Stabilität ihrer Substrate regulieren, verändern aber auch Eigenschaften und Strukturvon Proteinen, die mit Krankheiten assoziiert sind. Ein wichtiges Kennzeichen der Parkinson-Krankheit ist die Akkumulation von Proteinaggregaten (Lewy Körperchen). Dies führt zu neuronalem Zelltod durch verschiedene, bisher oft unbekannte Mechanismen. α-Synuclein, ein präsynaptisches, neuronales Protein, ist der Hauptbestandteil der Lewy-Körperchen und spielt eine wichtige Rolle in der Pathogenese der Parkinson-Krankheit. Es unterliegt verschiedenen posttranslationalen Modifikationen unter pathologischen Bedingungen. Die Zytotoxizität und Aggregation von α-Synuclein kann in Hefe imitiert werden. In dieser Studie werden zwei wichtigen posttranslationalen Modifikationen von α-Synuclein, Sumoylierung und Phosphorylierung von Serin 129 (S129), untersucht. Heterolog exprimertes Wildtyp-α-Synuclein und die A30P Mutante sind in Hefe an den gleichen Resten, Lysin 96 (K96) und Lysin 102 (K102), sumoyliert wie im Menschen. Eine Absenkung des zellulären Pools des Ubiquitin-ähnlichen Proteins SUMO führte zu einer starken Wachstumsreduktion von Zellen, welche α-Synuclein exprimieren. Dies korrelierte mit einer erhöhten Zahl an Zellen, die Einschlüsse bildeten. Dies legt nahe, dass Sumoylierung die Hefen vor α-Synuclein vermittelter Toxizität und Einschlussbildung schützt. Die Expression von sumoylierungsdefizienten α-Synuclein verursachte die gleiche Wachstumsrate, was die protektive Rolle der α-Synuclein Sumoylierung in cis bestätigt. Eine Überexpression der humanen Kinasen GRK5 und PLK2 erhöhten den Anteil an S129 phosphoryierten α-Synuclein. Interessanterweise wurde die α-Synuclein–vermittelte Zytotoxizität in Zusammenhang mit einer beeinträchtigten Sumoylierung durch eine höhere Kinase-abhängige S129 α-Synuclein Phosphorylierungsrate kompensiert. Phosphorylierung reduzierte die Einschlussbildung und verminderte die Wachstumshemmung. Um mehr Einblicke in eine plausible wechselseitige Beeinflussung zwischen α-Synuclein Sumoylierung und S129 Phosphorylierung zu erhalten, wurde die Beseitigung der α-Synuclein Aggregate beobachtet. Promotor „shut-off“ Studien wurden parallel mit chemischer Inhibition der zellulären Abbauwege durchgeführt. In der Abwesenheit von SUMO wurden α-Synuclein-Aggregate hauptsächlich durch das Ubiquitin-Proteasom-System abgebaut. Dies legt nahe, dass Sumoylierung den Abbau der α-Synuclein-Aggregate durch Autophagie unterstützt. In Anwesenheit der humanen Kinasen GRK5 oder PLK2, wurden die sumoylierungsdefizienten α-Synuclein-Aggregate Kinasen abhängig sowohl dem Ubiquitin-Proteasom als auch dem Autophagie-System zugeführt. Dies ging einher mit einem veränderten Ubiquitinierungs-Profil von α-Synuclein. GRK5 war in der Lage den Abbau von sumoylierungsdefizienten α-Synuclein-Aggregaten durch Autophagie partiell zu retten und außerdem das Proteasom-System zu unterstützen. In Abwesenheit von SUMO, wenn PLK2 überexprimiert wird, trugen beide Abbauwege gleich stark zur Beseitigung der α-Synuclein-Aggregate bei. Diese wechselseitige Beeinflussung zwischen α-Synuclein Phosphorylierung und Sumoylierung könnte neue Wege für eine therapeutische Intervention in der Parkinsonkrankheit und anderen Synucleinopathien eröffnen.

Thesis (doctoral)--University of Turku. / Bibliography: p. 100-115.

Parkinson’s disease is among the commonest debilitating neurodegenerative disorders. The disease is characterised by severe motor symptoms, including uncontrollable tremor, postural instability, slowness of movement and rigidity. The prominent pathological hallmark of the disease is a pronounced loss of dopamine-producing neurons in the substantia nigra (SN), which results in a drastic decrease in dopamine in the striatum, to which these neurons project. The etiology of disease progression has not yet been fully understood. A number of hypotheses have implicated environmental toxins including metals, pesticides etc and genetic factors to play a role in pathogenesis of PD. It is proposed that a cross-talk of environmental and genetic factors may also be involved. A variety of mechanisms that are believed to cause accelerated cell death have also been suggested, including oxidative stress, excitotoxicity and mitochondrial dysfunction and inflammation. Inflammatory pathways have emerged as primary players in the degenerative process seen in Parkinson’s disease. This study focuses on the role of inflammatory pathways, in particular those mediated via S100B, HMGB1 and TWEAK. S100B has been implicated in stroke, cerebral ischemia and in Alzheimer’s disease. HMGB1 a chromatin binding protein was also shown to be involved in stroke, sepsis and more recently Alzheimer’s disease. TWEAK signalling pathway is activated in tumour progression. Thus all of these proteins have been implicated in inflammation seen in a number of diseases. All these proteins have been looked at individually, but their role in neuroinflammation seen in PD is not yet completely understood. This was the main reason we selected these proteins. MPTP, a neurotoxin mimics parkinsonian conditions and has been widely used as a toxin model. In this study we assess the importance of S100B, HMGB1 and TWEAK using the MPTP mouse model of PD.

Made available in DSpace on 2019-03-30T00:11:58Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-08-17 / Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting the central nervous system. The motors signs of PD are bradykinesia, muscular rigidity, postural instability and resting tremor, which may lead changes in anatomical elements and dynamics of the temporomandibular joint (TMJ) and contribute to the emergence of temporomandibular disorders (TMD). Involuntary jaw movements and orofacial muscles rigidity may contribute to orofacial pain, increasing TMD painful symptoms. Objective: to evaluate the frequency of the signs, symptoms and diagnosis of TMD in individuals with Parkinson's disease in the Hospital Geral de Fortaleza (HGF), to determine DTM¿s subtypes in this population and to compare this findings to a control group. Methods: We evaluated TMD in 100 individuals between 50 and 88 years old, regardless of gender, based on the Diagnostic Criteria for Research on Temporomandibular Dysfunction (RDC/TMD). Individuals were selected, paired by age and gender, to two groups: a group with PD and a control group. The PD group consisted of 50 individuals, from which 23 had mandibular tremor. The control group included 50 individuals without significant neurological disease, recruited from NAMI (Núcleo de Atenção Médica Integrada) of the Universidade de Fortaleza (UNIFOR) and of the Centro de Saúde de Pindoretama. Data collection was performed by filling out a proper form for each individual. All analyzes were carried out considering a 95% confidence interval using the Statistical Packcage software for the Social Sciences (SPSS) version 17.0 for Windows. Results: PD patients had a higher frequency of clicking or popping (p=0,004) in the jaw joint when they opened or closed their mouth or during chewing; clenching or nocturnal teeth grinding (bruxism) (p=0,003) and uncomfortable or different bite (p=0,014) when compared to the control group. Two TMD subtypes were diagnosed (myofascial pain and disc displacement with reduction) in PD patients. Conclusion: Despite the higher frequency of some TMD symptoms in PD, no significant differences were found in the diagnosis and subtypes of TMD. This study leaves some questions to be answered, especially regarding the prognostic value of these findings. Literature on oral health in PD patients is still lacking, specially involving TMD. Unfortunally, these symptoms may cause a significant impairment in patients¿s fonation and quality of life. Key Words: Tempormandibular Dysfunction; Parkinson's disease; Mandibular Tremor. / Introdução: A Doença de Parkinson (DP) é a segunda afecção neurodegenerativa que mais comumente afeta o sistema nervoso central. Os pacientes podem apresentar sinais motores como bradicinesia, rigidez muscular, instabilidade postural e tremor de repouso, podendo levar a alterações em elementos anatômicos e na dinâmica da articulação temporomandibular (ATM) e contribuir para o surgimento de transtornos dessa articulação, como a disfunção temporomandibular (DTM). Além disso, movimentos mandibulares involuntários e rigidez da musculatura orofacial podem causar dor orofacial, contribuindo para a sintomatologia dolorosa da DTM. Objetivos: Avaliar a frequência de sinais, sintomas e diagnóstico de DTM em indivíduos com DP do Hospital Geral de Fortaleza (HGF), determinar os tipos de DTM encontrados nessa população e comparar esses achados com o grupo controle. Metodologia: Consistiu na avaliação da DTM em 100 indivíduos, entre 50 anos e 88 anos de idade, independente do gênero, pelos Critérios de Diagnóstico em Pesquisa para Disfunção Temporomandibular (RDC/TMD). Foram selecionados indivíduos para os dois grupos, pareados para idade e sexo: o grupo com DP (PDP) e o grupo controle. O grupo PDP foi formado por 50 indivíduos, dos quais 23 possuíam tremor mandibular. O grupo controle abrangeu 50 indivíduos sem doença neurológica significativa, recrutados do NAMI (Núcleo de Atenção Médica Integrada) da Universidade de Fortaleza (UNIFOR) e do Centro de Saúde de Pindoretama. A coleta de dados foi feita através do preenchimento de um formulário para os indivíduos de ambos os grupos. Todas as análises foram realizadas considerando uma confiança de 95% utilizando o software Statistical Package for the Social Sciences (SPSS) versão 17.0 para Windows. Resultados: Pacientes com DP apresentaram maior frequência de click ou estalido (p=0,004) ao abrir a boca, fechar a boca ou durante a mastigação, de ranger ou apertar os dentes noturno (bruxismo) (p=0,003) e de mordida desconfortável (p=0,014) quando comparados ao grupo controle. Foram encontrados dois tipos de diagnóstico de DTM (dor miofascial e deslocamento do disco com redução). Não foram encontradas diferenças significativas na frequência do diagnóstico de DTM, quanto à presença de dor secundária à disfunção e consequentemente escore na classificação de dor crônica. Conclusão: Apesar da maior frequência de alguns sintomas da DTM nos pacientes com Parkinson, na amostra não houve diferença significativa na frequência do diagnóstico nem quanto aos tipos de DTM. O presente estudo abre vários questionamentos, principalmente quanto ao caráter prospectivo desses achados, sendo necessário o desenvolvimento de estudos abordando essa temática. A literatura sobre saúde bucal em pacientes com DP, com ênfase em DTM, ainda é muito escassa e esses sintomas podem ter repercussão significativa sobre a qualidade de vida e funções fonatórias desses pacientes. Palavras chaves: Disfunção Temporomandibular; Doença de Parkinson; Tremor Mandibular.