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Implications for Parkinson's Disease Identification of parkin interactions: implications for Parkinson’s disease William Lloyd Haylett Dissertation presented for the degree Doctor of Philosophy in Science (Human Genetics) in the Faculty of Medicine and Health Sciences at Stellenbosch University Supervisor: Prof. Soraya Bardien Co-supervisors: Dr. Craig Kinnear and Prof. Jonathan Carr December 2015 Stellenbosch University https://scholar.sun.ac.za DECLARATION By submitting this thesis electronically, I declare that the entirety of the work contained therein is my own, original work, that I am the sole author thereof (save to the extent explicitly otherwise stated), that reproduction and publication thereof by Stellenbosch University will not infringe any third party rights and that I have not previously in its entirety or in part submitted it for obtaining any qualification. Signature: …………………………………….. Date: ……………………………… Copyright © 2015 Stellenbosch University All rights reserved Stellenbosch University https://scholar.sun.ac.za 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 Stellenbosch University https://scholar.sun.ac.za 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. Stellenbosch University https://scholar.sun.ac.za 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. Stellenbosch University https://scholar.sun.ac.za 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
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