The research reported here deals with the early characterization of Parkinson’s disease (PD), the second most common degenerative disease of the human motor system after Alzheimer’s. PD results from the death of dopaminergic neurons in the substantia nigra region of the brain. Its occurrence is highly correlated with the aging population whose numbers increase with the healthcare benefits of a longer life. Observation of motor control symptoms associated with PD, such as gait and speech analysis, is most often used to evaluate, detect, and diagnose PD. Since speech and some delicate motor functions have provided early detection signs of PD, reliable analysis of these features is a promising objective diagnostic technique for early intervention with any remedial measures. We implement and study here three PD diagnostic methods and their correlation between each other’s results and with the motor functions in subjects diagnosed with and without PD. One initial test documented well in the literature deals with feature analysis of voice during phonation to determine dysphonia measures. Features of the motor function of two fingers were extracted in tests titled “Motor function of alternating finger tapping on a computer keyboard” and “Motor function of the index and thumb finger tapping with an accelerometer”, that we objectively scripted. The voice dysphonia measures were extracted using various software packages like PRAAT, Wavesurfer, and Matlab. In the initial test, several robust feature selection algorithms were used to obtain an optimally selected subset of features. We were able to program distance classifiers, support vector machine (SVM), and hierarchical clustering discrimination approaches for the dichotomous identification of non-PD control subjects and people with Parkinson’s (PWP). Validation tests were implemented to verify the accuracy of the classification processes. We determined the extent of functional agreement between voice and motor functions by correlating test results.

Parkinson’s disease causes among other symptoms also writing disorder. Parkinson's dysgrafia is disease the writing of parkinsonics. The aim of the work is to show the importance of examinig the parametres of Parkinson's dysgrafia and to find writing parametres, which could distinguish healthy subjects from the pacient and also it could monitoring progress of pakinson's disease. Some of the parametrs showed marked differences and therefore could distinguish healthy people from those with Parkinson’s disease.

Midbrain dopamine neurons play a critical role in motor function, motivation, reward, and cognition by providing modulatory input to cortical and basal ganglia circuits. Given the importance of dopamine neurotransmission and its dysregulation in disease, mechanistic insight into the molecular underpinnings of dopaminergic neuronal function is needed. This thesis seeks to advance our understanding of dopamine neuronal cell biology by developing and applying cutting edge molecular profiling methods to study the subcellular translatome and proteome of dopamine neurons in mice. Chapter 1 provides an overview of the anatomy and cell biology of midbrain dopamine systems, with a particular emphasis on dopamine neurotransmission, neuronal heterogeneity, and selective vulnerability in Parkinson’s disease. Chapter 2 focuses on methods for studying local translation in neurons and describes newly discovered artifacts associated with two of these methods. Chapter 3 describes a global analysis of ribosome and mRNA localization in dopamine neurons; the results suggest that local translation in dopaminergic dendrites, but not axons, regulates dopamine release. Chapter 4 presents a method for subcellular proteomic profiling of dopamine neurons in the mouse brain, revealing the somatodendritic and axonal polarization of proteins encoded by Parkinson’s disease-linked genes. Emerging data are presented on Synaptotagmin 17, a novel axonal protein identified in midbrain dopamine neurons. Finally, I synthesize key findings regarding the molecular organization underlying dopamine neuronal cell biology and highlight promising areas for future investigation.

Parkinson’s disease (PD) is characterized by the degeneration of midbrain dopaminergic neurons. Genetic studies have revealed causative and risk loci associated with a proportion of PD cases, such as PRKN/PARK2, encoding parkin and when mutated causes a rare familial form of autosomal recessive PD. Cell-based studies have linked parkin to mitochondrial turnover by autophagy, but to date, manipulating this gene in rodents has not robustly recapitulated core features of PD. Reconciling these results is essential to determine parkin’s role in mitochondrial biology, brain physiology, and PD pathogenesis. Here, we find that global, inducible deletion of Prkn/Park2 (parkin iKO) in the adult mouse leads to age-dependent motor impairments that are responsive to levodopa treatment. We report that these behavioral defects are associated with progressive pathology in dopaminergic neurons, regional gliosis and lipid oxidation changes, culminating in the selective degeneration of nigrostriatal dopaminergic neurons. We also present a new, in vivo mitophagy reporter system to investigate the relationship of parkin’s described roles in mitochondrial homeostasis to the observed phenotypes. These results give critical insight into parkin’s contribution to dopaminergic neuron stability in the mammalian brain, and provide two distinct and novel organismal tools to investigate mitochondrial homeostasis and PD pathogenesis.

Thesis (PhD )--University of Stellenbosch, 2011. / ENGLISH ABSTRACT: Parkinson’s disease (PD), a neurodegenerative movement disorder characterized by resting tremors, bradykinesia, postural instability and rigidity, is due to a selective loss of dopaminergic neurons in the substantia nigra. Non-motoric symptoms include autonomic, cognitive and psychiatric problems. PD has been suggested to result from environmental factors, genetic factors or a combination of the two. Evidence has mounted over the last 13 years supporting the involvement of a significant genetic component. Mutations in the parkin, PINK1, DJ-1, ATP13A2, SNCA, and LRRK2 genes have been conclusively associated with PD. The aim of the present study was to establish the first study on the genetic etiology of PD in South African patients. Patients from the various South African ethnic groups with predominantly early-onset PD and/or a positive family history were recruited. Varying numbers of study participants (ranging from 88-205) were used for the different sections of this study depending on their availability at the time of the experiments and the specific clinical criteria applied. Mutation screening was conducted using High-resolution melt (HRM) analysis, DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). HRM analysis and sequencing of the known PD genes identified the following mutations: parkin (T113fsX163), PINK1 (Y258X), and LRRK2 (G2019S and R1441C). Using haplotype analyses, the five South African LRRK2 G2019S-positive patients were found to share a common ancestor with other G2019S haplotype 1-associated families reported worldwide. Two commercially available MLPA kits, SALSA P051 and P052, were used to assess the study participants for exon dosage mutations. Exonic deletions and insertions in parkin were identified in five patients. In addition, a family with a whole-gene triplication mutation of SNCA was identified. This is the 4th family worldwide to have this specific mutation which leads to a severe phenotype with autonomic dysfunction and early-onset dementia. The CAESAR (CAndidatE Search And Rank) bioinformatic program was used to select novel candidate genes for PD. CAESAR produced a ranked list containing known PD causing genes as well as novel candidates. The MAPT and SNCAIP genes were selected from the list of ten highest scoring genes. HRM analysis identified novel sequence variants in both genes with unknown functional significance that warrants further study. A novel 16bp deletion (g.-6_+10del) in the promoter region of DJ-1 was identified in one PD patient. The functional significance of this variant was investigated using a Dual-Luciferase Reporter assay. The variant was found to significantly reduce luciferase activity in two separate cell lines, HEK293 and BE(2)-M17 neuroblastoma cells, both with and without oxidative stress (p<0.0001), and we proposed that the 16bp sequence might be important in transcriptional regulation of DJ-1. In addition, the activity of three transcription factors (AhR, ARNT and HIF- 1) with binding sites within the deletion sequence may be influenced by the variant. In conclusion, mutation screening resulted in the identification of mutations in six patients in parkin, six patients in LRRK2, one patient in PINK1 and one patient in SNCA. In addition, a number of novel sequence variants were identified with unknown functional significance. Investigating the genetic basis of PD in the unique South African ethnic groups has shown that the known PD associated genes play minor roles in causing the disease in this population which indicates the possible involvement of other as yet unidentified PD genes. Innovative bioinformatic and wet bench experimental strategies are therefore urgently needed to identify new candidate genes for PD. / AFRIKAANSE OPSOMMING: Parkinson se siekte (PS), ‘n neurodegeneratiewe bewegings-siekte, gekarakteriseer deur rustende spiersametrekkings, bradykinesia, posturale onstabiliteit en rigiditeit, onstaan as gevolg van geselekteerde verlies van dopaminergiese neurone in die substantia nigra. Nie-motoriese simptome sluit in outonome, kognitiewe en psigiatriese afwykings. Dit is voorgestel dat PS ontwikkel as gevolg van omgewings- en genetiese faktore of ‘n kombinasie van die twee. Daar was ‘n toename in bewyse vir die verantwoordelikheid van die genetiese komponent oor die afgelope 13 jaar. Mutasies in die parkin, PINK1, DJ-1, ATP13A2, SNCA, en LRRK2 gene word met PS geassosieer. Die doel van hierdie studie was om vir die eerste keer die genetiese etiologie van PS in Suid- Afrikaanse pasiënte te ondersoek. Pasiënte van die verskillende Suid-Afrikaanse etniese groepe, met hoofsaaklik vroeë-aanvang PS en/of ‘n positiewe familie-geskiedenis, was gebruik. Wisselende getalle van studie-deelnemers (van 88-205) was gebruik vir die verskillende dele van die studie, afhangende van hul beskikbaarheid op die tyd van die eksperimente en die spesifieke kliniese kriteria wat van toepassing was. Mutasie-analiese was uitgevoer deur middel van Hoëresolusie smelting (HRS)-analiese, DNS volgorde-bepaling en multipleks ligasie-afhanklike ‘probe’ amplifikasie (MLPA). HRS-analiese en DNS volgorde-bepaling van die bekende PS gene het die volgende mutasies deïdentifiseer: parkin (T113fsX163), PINK1 (Y258X), en LRRK2 (G2019S en R1441C). Haplotiepe-analiese het gevind dat vyf Suid-Afrikaanse LRRK2 G2019S patiente ‘n gemeenskaplike voorvader deel met ander wêreldwyd gerapporteerde LRRK2 haplotiepe 1- geassosieerde families. Twee kommersieel beskikbare MLPA ‘kits’, SALSA P051 en P052, was gebruik om die deelnemers te toets vir exon-dosis mutaties. Exon-delesies en invoegings in parkin was gevind in vyf patiente. ‘n Familie met ‘n volle geen triplikasie van SNCA was gevind. Dit is die 4de familie wêreldwyd wat die spesifieke mutasie het en dit lei tot ‘n erge fenotiepe met outonomiese afwykings en vroeë-aanvang dementia. Die ‘CAESAR (CAndidatE Search And Rank)’ bioinformatiese program was gebruik om nuwe kandidaat PS gene te selekteer. Die program het ‘n lys kandidaat gene, wat beide bekende geassosieerde en nuwe bevat, opgelewer. Die MAPT en SNCAIP gene was gekies uit tien gene met die hoogste tellings. HRS analiese het nuwe DNS volgorde variante in beide gene gevind. Die funksies van die variante is tans onbekend en moet verder ondersoek word. ‘n Onbekende 16bp delesie (g.-6_+10del) in die promotor area van DJ-1 was gevind in een PS patient. ‘n Dubbel-lusiferase rapporteerder eksperiment was uitgevoer om die funksie van die variant te ondersoek. Die variant het die lusiferase-aktiwiteit aansienlik verlaag in twee afsonderlike sel lyne, HEK293 en BE(2)-M17 neuroblastoma selle, met en sonder oksidatiewe spanning (p<0.0001). Dit was voorgestel dat die 16bp volgorde dalk belangrik kan wees vir transkripsionele regulasie van DJ-1. Die variant mag dalk ook die aktiwiteit van drie transkripsie faktore (AhR, ARNT and HIF-1) met bindings plekke in die delesie- volgorde, beïnvloed. Ter afsluiting, mutasie analiese het gelei tot die identifikasie van mutasies in ses patiente in parkin, ses patiente in LRRK2, een patient in PINK1 en een patient in SNCA. ‘n Aantal nuwe variante was gevind met ombekende funksies. Ondersoek van die genetiese basis van PS in die uniek Suid-Afrikaanse etniese groepe het gevind dat die bekende PS gene nie ‘n groot rol speel in die ontwikkeling van die siekte in die populasie nie. Dit is moontlik dat ander onbekende PS gene hier verantwoordelik is vir die siekte. Dit is dus belangrik om innoverende bioinformatiese en eksperimentele strategieë toe te pas om nuwe kandidaat-gene, vir PS, te identifiseer. / University of Stellenbosch / Agence Nationale de la Recherche, France / South African Medical Research Council / Doris Crossley Foundation

Diploma project, the issue of informal care for a close person with Parkinson's disease from the perspective of caregivers is focused on the intensity of care and access to services that could help informal caregivers in the care of their loved ones.In the theoretical section of Parkinson's disease I am describing, its development and changes that the disease brings along. Then I followed with the care of relatives person and support from the social system - the state. In the practical part I have chosen for my research a survey, which was attended by only a small part of respondents from informal carers. Care of long-term sick family member is very difficult. Caregivers feel tired and exhausted, they report that their own health becomes wors. Care also affects cares professional life and there leisure time. Although half of the respondents are still able to find time for their hobbies. Some carers have no idea about the possibilities of helping services and just minimum of them use these services.

BACKGROUND: Elderly individuals with type 2 diabetes mellitus (T2DM) suffer from several comorbidities, which affect their health outcomes, as well as process of care. This study assessed process and intermediate clinical outcomes of diabetes care among elderly individuals with T2DM and co-occurring Parkinson's disease(PD). METHODS: This study used a retrospective cohort design with propensity score matching using Humana Medicare Advantage Part D claims database (2007-2011) and included elderly (age ≥ 65 years) Medicare beneficiaries with T2DM (identified by ICD-9-CM code of 250.x0 or 250.x2). PD was identified using ICD-9-CM code of 332.xx. After propensity score matching there were 2,703 individuals with T2DM and PD and 8,109 with T2DM and no PD. The three processes of care measures used in this study included: (i) HbA1c test; (ii) Lipid test; (iii) and Nephropathy screening. Intermediate clinical outcomes consisted of glycemic and lipid control. RESULTS: Multivariable conditional logistic regressions revealed that elderly individuals with T2DM and PD were 12 % (AOR: 0.88, 95 %CI: 0.79-0.97) and 18 % (AOR: 0.82, 95 %CI: 0.72-0.94) less likely to meet the annual American Diabetes Association (ADA) recommended HbA1c and lipid testing goals respectively compared to individuals with T2DM and no PD. Multinomial conditional logistic regressions showed that elderly individuals with T2DM and PD were more likely to have HbA1c and lipid (HbA1c < 8 %; LDL-C <100 mg/dl; HDL-C ≥ 50 mg/dl; triglyceride <150 mg/dl; and total cholesterol <200 mg/dl) control. CONCLUSIONS: Among elderly individuals with T2DM, those with PD were less likely to achieve ADA recommended annual HbA1c and lipid testing compared to those without PD. However, PD individuals were more likely to achieve intermediate glycemic and lipid control.

Neurological diseases are devastating illnesses that affect over one billion people worldwide. Drosophila melanogaster provides a genetically tractable system in which to study gene function and the mechanisms of pathogenesis of neurological diseases. In this study I have investigated the function of survival motor neuron (SMN), the causative gene in the neuromuscular disease spinal muscular atrophy (SMA), in growth and differentiation in Drosophila. In addition, I have used the fruit fly to investigate a putative modifier of a previously characterised Drosophila model of Parkinson's disease. Spinal muscular atrophy is an autosomal recessive neurological disease that is characterised by motor neuron loss resulting in muscle weakness. The disease is caused by the deletion or mutation of the survival motor neuron (SMN) gene. In Drosophila, SMN was found to be highly expressed in dividing tissues and a reduction in SMN levels resulted in growth defects, stem cell defects and developmental delay. SMN was also shown to regulate chromosome morphology of the endocycling nurse cells of the female germline. Therefore it appears that SMN has a role in growth control and development in Drosophila. Parkinson's disease is a common disorder that results in widespread neurodegeneration with a predilection for dopaminergic neuron loss resulting in movement defects. A defining neuropathological feature of the disease is the presence of alpha-synuclein containing inclusions. Using a Drosophila model of PD, I have shown that specific alpha-synuclein-induced phenotypes in the fly can be suppressed by the overexpression of the E3 ubiquitin ligase, Nedd4.

Thesis (PhD)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Parkinson’s disease (PD) is a progressive and debilitating neurodegenerative disorder, characterized by a distinct motor phenotype and the selective loss of dopaminergic neurons in the substantia nigra. While the etiology of PD is not fully understood, it is thought to involve a combination of different genetic, cellular and environmental factors that independently or concurrently contribute to neurodegeneration. To date, several PD-causing genes have been identified, and investigations of their function have provided novel insights into the pathobiology of disease. Particularly interesting among the known PD genes is parkin, mutations in which are the most common genetic cause of early onset PD. Parkin is an E3 ligase that ubiquitinates protein substrates and targets such substrates for degradation via the ubiquitin proteasome system (UPS). Therefore, the loss of parkin may result in the deleterious accumulation or dysregulation of parkin substrates and neurotoxicity. Parkin’s enzymatic activity has also been implicated in the maintenance of mitochondrial health, and mitochondrial dysfunction is commonly reported in cellular and animal models of parkin deficiency. This study aimed to investigate parkin and its role in PD on various levels. Initially, genetic screening approaches were used to assess the contribution of parkin mutations to PD in a group of 229 South African patients. It was concluded that parkin mutations are rare in the South African PD population, being present in only seven (3.1%) patients in the study group. Interestingly, this study identified two of only three Black African PD patients with mutations in a known PD-causing gene to date. The low frequency of known PD genes raises the interesting possibility that the unique South African ethnic groups may harbor mutations in novel PD-causing genes. Although many parkin-interacting proteins have been identified in the literature, it is anticipated that novel, pathologically-relevant parkin substrates remain to be discovered. Hence, this study used a yeast two-hybrid (Y2H) approach to identify novel parkin interactions. This yielded 29 putative parkin interactors, of which four, namely ATPAF1, SEPT9, actin and 14-3-3η, were prioritized for verification by co-localization and co-immunoprecipitation experiments. Interestingly, two of the parkin interactors (ATPAF1 and SEPT9) were found to accumulate in the absence of parkin, supporting their role as authentic parkin substrates. The identification of these two intriguing proteins implicates parkin in the regulation of mitochondrial ATP synthase assembly and septin filament dynamics, which may be of significant relevance to our understanding of processes underlying neurodegeneration. Moreover, it was aimed to assess various markers of mitochondrial function in a parkin-deficient cellular model, as previous studies had reported conflicting results regarding mitochondrial impairments in patient-derived cells with parkin mutations. Hence, dermal fibroblasts were obtained from PD patients with homozygous parkin mutations, after which cell growth and viability, mitochondrial membrane potential, respiratory rates and the integrity of the mitochondrial network were assessed. Surprisingly, it was found that cell growth was significantly higher in the parkin-mutant fibroblasts compared to wild-type controls fibroblasts under basal conditions (p=0.0001), while exhibiting a greater inhibition of cell growth in the presence of the mitochondrial toxin CCCP (p=0.0013). Furthermore, whereas the mitochondrial networks of patient-derived fibroblasts were more fragmented than controls (p=0.0306), it was found that mitochondrial respiratory rates were paradoxically higher in the patients (p=0.0355). These unanticipated findings are suggestive of a compensatory response to the absence of parkin. The parkin-deficient cellular model was also used in a pilot study of the functional effects of vitamin K2 treatment, which has recently been identified as a promising PD therapeutic modality. It was found that treatment with vitamin K2 resulted in more interconnected mitochondrial networks (p=0.0001) and enhanced respiratory rates (p=0.0459) in both parkin-mutant and wild-type control cells. While these results need to be studied further, it suggests that vitamin K2 supplementation may be of use as a general promoter of mitochondrial integrity and function. In conclusion, this dissertation highlights some novel interactions of the parkin protein and some interesting phenotypes of parkin deficiency. It is hoped that further investigation of parkin and its role in PD will, ultimately, aid in the development of therapeutic strategies to treat this debilitating and poorly-understood disorder. / AFRIKAANSE OPSOMMING: Parkinson se siekte (PS) is 'n progressiewe en aftakelende neurodegeneratiewe kondisie, wat gekarakteriseer word deur 'n kenmerkende bewegingsfenotipe en die selektiewe afsterwing van dopaminergiese neurone in die substantia nigra. Terwyl die etiologie van PS nie ten volle verstaan is nie, behels dit waarskynlik 'n kombinasie van verskillende genetiese, sellulêre en omgewings-faktore wat onafhanklik of gelyktydig lei tot senuwee-afsterwing. Tot op hede is daar al verskeie PS-veroorsakende gene geïdentifiseer, en die bestudering van hul funksie het nuwe insigte in die patobiologie van hierdie siekte verskaf. Onder meer hierdie PS gene is parkin van besondere belang, aangesien mutasies in parkin die mees algemene genetiese oorsaak van vroeë-aanvang PS is. Parkin is 'n E3 ligase-ensiem wat proteïen substrate ubiquitineer en teiken vir degradasie via die ubiquitien proteasoomstelsel (UPS). Dus kan die verlies van parkin lei tot die beskadigende opeenhoping of wanregulasie van parkin substrate en senuwee-afsterwing. Parkin se ensiematiese aktiwiteit is ook betrokke by die instandhouding van mitokondriale gesondheid, en mitokondriale afwykings word dikwels gerapporteer in sellulêre en diermodelle van parkin tekort. Hierdie studie het gepoog om parkin en sy rol in PS op verskillende vlakke te ondersoek. Aanvanklik is genetiese siftingsbenaderinge gebruik om die bydrae van parkin mutasies tot PS in 'n groep van 229 Suid-Afrikaanse pasiënte te evalueer. Die gevolgtrekking is bereik dat parkin mutasies skaars is in die Suid-Afrikaanse PS bevolking, aangesien dit teenwoordig is in net sewe (3.1%) pasiënte in die studie groep. Interessant genoeg, hierdie studie het twee van slegs drie gevalle van Swart Afrika-pasiënte met mutasies in 'n bekende PS geen to op datum geïdentifiseer. Die lae frekwensie van bekende PS gene versterk die stimulerende moontlikheid dat die unieke Suid-Afrikaanse sub-populasies dalk mutasies in nuwe PS-veroorsakende gene mag koester. Alhoewel baie parkin proteïen-interaksies reeds in die literatuur geïdentifiseer is, word daar verwag dat nuwe, patologies-relevante parkin substrate nog wag om ontdek te word. Dus het hierdie studie 'n gis twee-hibried (G2H) benadering gebruik om nuwe parkin interaksies te identifiseer. Hierdie het 29 vermeende parkin interaktors opgelewer, waarvan vier, naamlik ATPAF1, SEPT9, aktien en 14-3-3η, geprioritiseer is vir verifikasie deur mede-lokalisering en mede-immunopresipitasie eksperimente. Interessant genoeg, daar is gevind dat twee van die parkin interaktors (ATPAF1 en SEPT9) ophoop in die afwesigheid van parkin, wat hul rol as werklike parkin substrate ondersteun. Die identifisering van hierdie twee interessante proteïene impliseer parkin in die regulering van mitokondriale ATP sintase vervaardiging en septienfilament dinamika, wat moontlik van beduidende belang is vir ons begrip van die onderliggende prosesse wat senuwee-afsterwing veroorsaak. Verder is daar daarop gemik om verskeie aanwysigings van mitokondriale funksie in 'n parkin-gebrekkige sellulêre model te evalueer, aangesien vorige studies teenstrydige resultate rapporteer rakende mitokondriale afwykings in pasiënt-selle met parkin mutasies. Dus is daar dermale fibroblaste verkry van PS pasiënte met homosigotiese parkin mutasies, waarna sel-groei en lewensvatbaarheid, mitokondriale membraanpotensiaal, respiratoriese tempo en die integriteit van die mitokondriale netwerk geëvalueer is. Daar is verbasend gevind dat sel-groei aansienlik hoër is die parkin-mutante fibroblaste in vergelyking met wilde-tipe kontrole fibroblaste onder basale kondisies (p=0.0001), terwyl hulle 'n groter inhibisie van sel-groei in die teenwoordigheid van die mitokondriale toksien CCCP ondergaan (p=0.0013). Verder, terwyl die mitokondriale netwerke van pasiënt fibroblaste meer gefragmenteer is as die van kontroles (p=0.0306), is daar gevind dat mitokondriale respiratoriese tempo’s, paradoksaal-gewys, hoër is in die pasiënte (p=0.0355). Hierdie onverwagte bevindinge is suggestief van die aanskakeling van 'n vergoedende respons-proses in die afwesigheid van parkin. Die parkin-gebrekkige sellulêre model is ook gebruik in 'n voorlopige studie van die funksionele effekte van vitamiene K2 behandeling, wat onlangs geïdentifiseer is as 'n belowende terapeutiese moontlikheid vir PS. Daar is gevind dat sel-behandeling met vitamiene K2 lei tot meer geïnterkonnekteerde mitokondriale netwerke (p=0.0001) en verbeterde respiratoriese fuksie (p=0.0459) in beide parkin-mutante en wilde-tipe kontrole selle. Terwyl hierdie resultate verder bestudeer sal moet word, dui dit daarop dat vitamiene K2-aanvulling moontlik gebruik kan word as 'n algehele promotor van mitochondriale integriteit en funksie. Ten slotte, hierdie verhandeling beklemtoon ‘n paar nuwe interaksies van die parkin proteïen en 'n paar interessante fenotipes van parkin tekort. Daar word gehoop dat verdere ondersoek van parkin en parkin se rol in PS sal, uiteindelik, steun in die ontwikkeling van terapeutiese strategieë om hierdie aftakelende en swak-verstaande wanorde beter te behandel.

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy