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

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.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Dissertation (Ph.D.).--University of Texas Graduate School of Biomedical Sciences at San Antonio, 2007. / Vita. Includes bibliographical references.

Thesis (M.S.)--University of Florida, 2005. / Typescript. Title from title page of source document. Document formatted into pages; contains 54 pages. Includes Vita. Includes bibliographical references.

Background: Gait impairments and postural deficits are very common in people with Parkinson Disease (PD), and also highly associated with fall risk and functional decline. Some evidence showed that in older adults, Nordic Walking (NW) could slow the progression of some gait impairments and increasing stride length and gait speed. Moreover, previous studies suggested that gait disturbances in PD are associated with less automatic gait performances and therefore gait requires more attention, as it is essential for regulation of postural balance. Further, research of this fact has very minimally been examined in PD population. Purpose: The purpose of this study is to investigate whether Nordic walking can improve gait pattern in individual with PD after a 6-week training program, as well as determine the effect of performing a cognitive task while walking with and without the poles on gait characteristics. Methods: Gait spatial temporal and kinetics data was collected with and without poles in 12 adults with PD (age: 61.58±11.7 years; 9 male, 3 female; Hoehn and Yahr scale 1-3 stage; UPDRS III average: 11; the year of diagnosis: 6.72 years). Participants performed six 5m walking trials; 3 with poles and 3 without after 6-week training. Participants also performed four 90 seconds walking trials on a 25m pathway in four different conditions: NP (no poles) and no cognitive task, NW (Nordic walking) and no cognitive task, NP and a cognitive task, NW and a cognitive task. For this latter part of the experiment, gait characteristics and trunk kinematics were quantified by using a 6 inertial sensor accelerometry system (APDM, Oregon, USA). As for the 5m tasks, gait spatial temporal and kinetics were collected with an eight cameras 3-dimensional motion capture system (Vicon, Oxford, UK) and 2 force platforms (Kistler, Winterthur, Switzerland). All variables were assessed using paired t-test to compare NW to conventional walking and two-way ANOVA to compare cognitive and pole conditions. Results: When comparing NW to NP, the results showed significantly longer stride length, and larger single support time. The data also showed larger knee power generation during mid-stance as well as decreased power absorption at the knee during swing. Moreover, when assessing the effect of performing a cognitive task on gait, gait speed and cadence in both normal walking and Nordic pole walking was significant smaller when performing the cognitive task. The trunk frontal range of motion (ROM) and velocity were smaller compared NW to NP. When adding cognitive tasks, trunk frontal ROM and velocity were significantly smaller. Conclusions: Based on the results, 16 self-directed sessions of NW can help improve certain gait spatial-temporal characteristics as well as some aspect of the gait pattern kinetics, especially at the knee. Moreover it seems that a 16 sessions (45mintues per session) or even longer practice period is necessary for NW beginner, in order to gain perfect technique and restore gait to a more normal pattern than novice.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009.

A thesis submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, for the degree of Doctor of Philosophy (Medicine) / Idiopathic Parkinson's disease remains one of the commonest neurodegenerative diseases known today. It causes incapacita ting symptoms untreated but when given replacement neurotransmitters, principally levodopa or dopamine, corrects the major features of the illness. The fundamental cause of nigral dopaminergic cell decline remains unknown, is not principally genetic, but may be due to abnormal hepatic handling of neurotoxins. One such putative neurotovin is MPTP which causes parkinsonism in man and primates. The MPTP-treated primate model is thus a useful model within which new drugs, including dopamine receptor agonists may be tested. Levodopa remains the mainstay of successful pharmacotherapy in the treatment of parkinson's disease. However the last decades have taught us that levodopa treatment with time produces problems of dyskinesias and unpredictable motor fluctuations. Hence alternate pharmacotherapy is sought to supplement levodopa or possibly to circumvent its necessity. (Abbreviation abstract) / Andrew Chakane 2019