Dissertations / Theses on the topic 'NF2/Merlin'

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2003.
Vita.
Includes bibliographical references.
The Neurofibromatosis type 2 tumor suppressor gene (NF2) is mutated in inherited and sporadically occurring central nervous system tumors. The NF2 encoded protein, merlin, shares close sequence similarity in its amino-terminal domain to members of the band 4.1 family of membrane-cytoskeletal linkers. Similarities between merlin and this family suggest a role for merlin in regulating cytoskeletal function. Thus, NF2 may be a novel type of tumor suppressor gene that mediates its tumor suppressor function through interactions with the actin cytoskeleton. However, the molecular and cellular functions of this tumor suppressor gene were largely unknown when the work described here began. Mutational analysis of Nf2 in flies has lead to the identification of a dominant-negative allele, which harbors mutations in the amino-terminal domain of the protein. The work presented here demonstrates that expression of a murine analog of this amino-terminal mutant of Nf2 (termed, Nf2BBA) leads to complete transformation of NIH3T3 fibroblasts in culture. Cells that express Nf2BBA display disruptions of the actin cytoskeleton, lack of contact inhibition of growth, and anchorage-independent growth. In addition, Nf2-deficient mouse embryo fibroblasts (MEFs) exhibited similar contact inhibition and cell-matrix adhesion defects to Nf2BBA expressing cells. Nf2BBA cells continue to cycle under normal growth inhibitory conditions, such as serum withdrawal, and exhibit high levels of the cell cycle regulator, cyclin D1. Elevated levels of cyclin D1 are necessary for cellular transformation following Nf2BBA expression. Nevertheless, the exact mechanism by which Nf2BBA results in cellular transformation remains elusive. Recently published studies have revealed that merlin may regulate members of the RhoGTPase
(cont.) family, as absence of Nf2 expression in fibroblasts leads to many phenotypes reminiscent of overactive Rac, such as increased membrane ruffling and increased activity of the c-jun N- terminal kinase (JNK). Our work has extended to the analysis of the role of merlin in the regulation of the Rac pathway. Using rat schwannoma cells and N2-deficient MEFs, we have demonstrated that merlin exerts its inhibitory effects downstream of Rac, through a direct interaction with the p21 activated kinase, Pak. We demonstrate that in the absence of merlin, Pak is active and hyperphosphorylated, and, conversely, when merlin is overexpressed, Pak activity is diminished. The N-terminal half of merlin binds to the functionally conserved Rac/Cdc42 interaction binding (CRIB) domain of Pak. Several models for merlin regulation of Pak activity will be discussed. Finally, the identification of Pak as a kinase that is misregulated in the absence of NF2 may lead to possible avenues for therapeutic intervention.
by Kristen C. Johnson.
Ph.D.

Dans le système nerveux central, la formation des gaines de myéline par les oligodendrocytes permet une propagation efficace et adaptée des potentiels d'action le long des axones, ainsi qu'un apport métabolique aux neurones. Le processus de myélinisation requière une fine régulation du cytosquelette d'actine des oligodendrocytes. En effet, la première étape de la myélinisation, qu'est l'extension d'un prolongement par les oligodendrocytes pour atteindre un axone, est soutenue par une polymérisation de l'actine. En revanche, l'enroulement de ce prolongement et son étalement autour de l'axone pour former cette structure multi-lamellaire qu'est la gaine de myéline nécessite une déconstruction drastique du cytosquelette d'actine. Les mécanismes moléculaires déclenchant ce passage vers la dépolymérisation de l'actine restent peu clairs. Néanmoins, leur identification est essentielle, car en plus de mieux comprendre les mécanismes sous-tendant la myélinisation, elle permettrait de trouver de nouvelles cibles thérapeutiques pour stimuler la formation et la réparation de la myéline dans les maladies qui l'affectent, qu'il s'agisse une perte de myéline comme dans la sclérose en plaques, ou une formation inadaptée de myéline par rapport aux besoins des circuits neuronaux comme dans les troubles du spectre autistique.Pendant la première partie de ma thèse, nous avons testé l'implication de la protéine PAK1 (P21 Activated Kinase 1) dans le contrôle de la myélinisation, agissant potentiellement comme levier permettant le passage à la dépolymérisation de l'actine. En effet, PAK1 est connue pour moduler les dynamiques de l'actine via son activité kinase : l'activer favorise le maintien du cytosquelette d'actine polymérisé, alors que l'inhiber permet son désassemblage. Au cours de la maturation des oligodendrocytes, nous avons montré que l'expression de PAK1 augmente, alors que son activité kinase est de plus en plus inhibée, ce qui est cohérent avec un potentiel rôle de PAK1 dans la myélinisation. De façon intéressante, nous avons montré qu'empêcher l'inhibition de PAK1 dans les oligodendrocytes in vitro restreint la dépolymérisation de l'actine et par conséquent l'expansion des membranes de myéline. À l'inverse, augmenter l'inhibition de PAK1 stimule la dépolymérisation de l'actine et l'expansion des membranes de myéline. Ainsi, l'inhibition endogène de PAK1 est nécessaire à la déconstruction du cytosquelette d'actine menant à la formation de la myéline. In vivo, la délétion de Pak1 dans les oligodendrocytes augmente spécifiquement l'épaisseur des gaines de myéline. Ensemble, ces résultats suggèrent que l'activité kinase de PAK1 doit nécessairement être inhibée pour stimuler la myélinisation. Ces observations impliquent également la présence d'un inhibiteur endogène de PAK1 dans les oligodendrocytes. Nos analyses ont mené à l’identification et la validation de NF2/Merlin. Nous avons montré que NF2/Merlin, en inhibant PAK1, régule la dynamique du cytosquelette d'actine dans l'oligodendrocyte et l'expansion des membranes de myéline in vitro. Ces résultats ont ainsi permis l'émergence d'un modèle mécanistique dans lequel l'action antagoniste de NF2/Merlin et PAK1 stimule la dépolymérisation de l'actine dans les oligodendrocytes, et donc l'expansion des membranes de myéline.Dans la seconde partie de ma thèse, qui est en cours, nous avons montré que NF2/Merlin contrôle la myélinisation développementale in vivo via des mécanismes dépendants et indépendants de l'axe PAK1/actine, impliquant notamment une modulation des microtubules.Dans l'ensemble, les résultats de ma thèse permettent de mieux comprendre les mécanismes sous-jacents de la myélinisation, qui pourraient également être étudiés dans le contexte de la remyélinisation
In the central nervous system, myelin sheath formation by oligodendrocytes ensures efficient and adapted propagation of action potentials, as well as metabolic support to neurons. Myelination is an intrinsic program of mature oligodendrocytes that requires precise modulation of their actin cytoskeleton. Indeed, the extension of the oligodendrocyte process to reach an axon is supported by actin polymerisation; whereas the extension and wrapping of oligodendrocyte membrane to form the concentric multi-layered membrane, that is myelin sheath, is supported by a drastic deconstruction of the actin cytoskeleton. The molecular mechanisms triggering this shift to actin depolymerisation remain unclear. Determining the mechanisms involved in this crucial process provides a better understanding of myelination and could pave the way for new therapeutic targets to stimulate myelin formation. This is of great importance for demyelinating diseases such as multiple sclerosis, and for neurodevelopmental diseases characterised by a mismatch of the amount of myelin formed to the needs of circuits, such as in autism spectrum disorders.During the first part of my thesis, we tested the involvement of P-21 activated kinase 1 (PAK1) in the regulation of myelination, hypothesising its potential control of actin dynamics. Indeed, PAK1 is known to regulate the actin cytoskeleton via its kinase activity: active PAK1 maintains actin cytoskeleton polymerised, while inhibited PAK1 stimulates its deconstruction. We showed that during oligodendrocyte maturation, PAK1 is increasingly expressed, yet its kinase activity is stronly inhibited, which is consistent with the potential role of PAK1 in regulating myelination. Moreover, we showed that maintaining PAK1 in an abnormal constitutively active form restrains actin deconstruction and myelin membrane expansion, whereas enhancing PAK1 inhibition increases myelin expansion via enhanced actin depolymerisation. Together, these results suggest that PAK1 endogenous inhibition is necessary for actin depolymerisation and subsequent myelin formation. In vivo, depleting Pak1 in oligodendrocytes specifically increases myelin thickness. Taken together, our findings suggest that to form the correct amount of myelin, PAK1 kinase activity must be inactivated, whether the protein is absent or inhibited. Moreover, this implies the presence of an endogenous PAK1 inhibitor in oligodendrocytes. We identified and validated NF2/Merlin as an endogenous inhibitor of PAK1 in oligodendrocytes, enabling actin depolymerisation and myelin membrane expansion. Overall, this initial study has led to the emergence of a mechanistic model in which the antagonistic actions of NF2/Merlin and PAK1 stimulates actin depolymerisation in oligodendrocytes and hence the formation of myelin membranes.In the second part of my thesis, currently in progress, we have shown that NF2/Merlin controls developmental myelination in vivo via PAK1/actin axis-dependent and -independent mechanisms, in particular involving microtubule modulation.Overall, the findings of my thesis provide a more comprehensive understanding of the underlying mechanisms of myelination, which could also be studied in the context of remyelination

Merlin is a tumour suppressor protein that is frequently mutated or downregulated in cancer. Biallelic Merlin inactivation is causative of tumour formation, including schwannoma, meningioma and ependymoma. These tumours can occur sporadically or as part of the genetic condition Neurofibromatosis type 2 (NF2) and cause significant morbidity. The current treatment options are restricted to surgery and radiotherapy, which are invasive and may cause further tumour development. The activity of both the E3 ubiquitin ligase complex Cullin 4 really interesting new gene (RING) E3 ubiquitin ligase- DNA damage binding protein (DDB1) and Cullin 4 associated factor 1 (CRL4-DCAF1) and Kinase suppressor of RAS 1 (KSR1) have been shown to be upregulated in schwannoma to drive tumour growth. KSR1 has also been shown to interact with components of the CRL4-DCAF1 complex. We investigated the expression, interaction and therapeutic potential of targeting these proteins in Merlin deficient schwannoma and meningioma using a primary human cell model and relevant cell lines. We found that DCAF1 and KSR1 protein were overexpressed in schwannoma and meningioma and confirmed that targeting both DCAF1 and KSR1 in meningioma had additive effects on proliferation. We also identified that CRL4-DCAF1 facilitates KSR1 dependent RAF/Mitogen-activated protein kinase (MAPK)/ Extracellular signal regulated kinase (ERK) kinase (MEK)/ERK pathway activity. We showed MLN3651, a neddylation inhibitor that targets ubiquitin ligase activity, reduced proliferation and activated apoptosis in Merlin-deficient tumours. We also showed that Merlin-positive tumours were less sensitive to MLN3651 than Merlin-deficient tumours; therefore, MLN3651 sensitivity may be CRL4-DCAF1-dependent. Finally, combination of MLN3651 and the MEK1/2 inhibitor AZD6244 had additive effects, particularly in meningioma. Combinatorial therapy activated the Hippo pathway, inhibited RAF/MEK/ERK pathway activity and proliferation demonstrating that targeting the activity and downstream pathways of both DCAF1 and KSR1 represents an attractive novel therapeutic strategy in Merlin-deficient tumours.

Veränderungen in phosphorylierungsabhängigen Signalwegen, Akkumulation von Proteinaggregaten im Gehirn und neuronaler Zelltod sind Neurodegenerationskennzeichen und Indikatoren für überlappende molekulare Mechanismen. Um Einblicke in die involvierten Signalwege zu erhalten, wurde mit Hilfe eines modifizierten Hefe-Zwei-Hybrid (Y2H)-Systems für 71 Proteine, die mit neurologischen Erkrankungen assoziiert sind, proteomweit nach Protein-Protein Interaktionen (PPIs) gesucht. Für 21 dieser Proteine wurden PPIs identifiziert. Das Gesamtnetzwerk besteht aus 79 Proteinen und 90 PPIs von denen 5 phosphorylierungsabhängig sind. Ein Teil dieser PPIs wurde in unabhängigen Interaktionsassays mit einer Validierungsrate von 66 % getestet. Der netzwerkbasierte Versuch verbindet erfolgreich neurologische Erkrankungen untereinander aber auch mit zellulären Prozessen. Ser/Thr-Kinase abhängige PPIs verknüpfen zum Beispiel das Parkinson Protein 7 (PARK7, DJ1) mit den E3 Ligase Komponenten ASB3 und RNF31 (HOIP). Die Funktion dieser Proteine bekräftigt den Zusammenhang zwischen dem Ubiquitin-Proteasom-System und der Parkinson Krankheit (PD). Neurofibromin 2 (NF2, merlin) Isoformen und PARK7 interagieren mit der regulatorischen PI3K Untereinheit p55-gamma (PIK3R3). Diese PPIs basieren auf Tyr-Kinase Aktivität im modifizierten Y2H System und funktionellen PIK3R3 pTyr-Erkennungsmodulen (SH2 Domänen) in co-IP und Venus PCA Versuchen. Dies verknüpft den PI3K/AKT Überlebenssignalweg mit zwei unterschiedlichen neurologischen Erkrankungsphenotypen: dem PD assoziierten neuronalen Zelltod und der Neurofibromatose Typ 2-assoziierten Tumorentstehung. Die vergleichende Beobachtung von PIK3R3, AOF2 (KDM1A, LSD1) Interaktionen auf NF2 Isoformlevel offenbart eine Bevorzugung von Isoform 7 bei zytoplasmatischer Lokalisation, wohingegen Isoform 1 PPIs an der Membran lokalisiert sind. Das modifizierungsabhängige und isoformspezifische PPI Netzwerk ermöglichte neue Hypothesen zu molekularen Pathomechanismen.
Alterations in phosphorylation-dependent signalling pathways, accumulation of aggregated proteins in the brain and neuronal apoptosis are common to neurodegeneration and implicate overlapping molecular mechanism. To gain insight into involved pathways, a modified yeast-two hybrid (Y2H) system was applied to screen 71 proteins associated with neurological disorders in a proteome-wide manner. For 21 of these proteins interactions were identified including 5 phosphorylation-dependent ones. In total, the network connected 79 proteins through 90 protein-protein interactions (PPIs). A fraction of these Y2H PPIs was tested in secondary interaction assays with a validation rate of 66 %. The described network-based approach successfully identified proteins associated with more than one disorder and cellular functions connected to specific disorders. In particular, the network revealed Ser/Thr kinase-dependent PPIs between the Parkinson protein 7 (PARK7, DJ1) and the E3 ligase components ASB3 and RNF31 (HOIP). The function of these proteins further substantiates the established connection between Parkinson’s disease (PD) and ubiquitination-mediated proteasome (dis)functions. Neurofibromin 2 (NF2, merlin) isoforms and PARK7 were identified as PI3K regulatory subunit p55-gamma (PIK3R3) interactors. These PPIs required Tyr kinase coexpression in the modified Y2H system and functional PIK3R3 pTyr-recognition modules (SH2 domains) in co-IP and Venus PCA experiments. This finding implicates the PI3K/AKT survival pathway in PD-associated neuronal apoptosis and Neurofibromatosis type 2-associated tumour formation. Investigation of PIK3R3, AOF2 (KDM1A, LSD1) and EMILIN1 PPIs on NF2 isoform level revealed preferential isoform 7 binding and cytoplasmic or membrane localisation of these PPIs for isoform 7 or 1, respectively. The generated modification-dependent and isoform-specific PPI network triggered many hypotheses on the molecular mechanisms implicated in neurological disorders.

Les schwannomes sont des tumeurs bénignes se développant à partir d’une hyper-prolifération des cellules de Schwann suite à l’inactivation bi-allélique du gène NF2. Signe pathogonomique d’une pathologie rare et héréditaire, la Neurofibromatose de type 2 (NF2), ils peuvent aussi apparaître de façon sporadique. Hormis la chirurgie ou la radiothérapie, peu d’options pharmacologiques sont proposées aux patients porteurs de schwannomes, principalement à cause du peu de cibles thérapeutiques identifiées. Dans les cellules de Schwann, le phénotype cellulaire associé à la perte NF2 est une perte d’inhibition de la prolifération par le contact. Deux fonctions majeures de Merlin, produit de NF2, ont émergé au cours de ces dix dernières années. La première, démontrée par notre groupe, concerne la régulation de l’expression membranaire des récepteurs à activité tyrosine kinase (RTK) qui s’accumulent à la membrane plasmique des schwannomes humains. Le second implique Merlin dans la régulation de la voie de signalisation Hippo. Cette dernière, activée par le contact cellulaire réprime l’activité de deux co-facteurs de transcription, Yap et Taz, et régule ainsi et aussi l’inhibition de contact. Les mécanismes moléculaires par lesquels Merlin inhibe l’activité de Yap/Taz sont toutefois méconnus. Le but de nos études a été de déterminer une signature moléculaire associée à la croissance des schwannomes humains et l’importance relative de Yap/Taz. Dans une analyse protéomique à grande échelle sur des biopsies humaines, nous avons identifié à la fois l’activation spécifique de cinq RTKs que sont le PDGFRβ, Her2, Her3, Axl et Tie2 ainsi qu’une accumulation nucléaire spécifique de Yap. Nous montrons que sur la totalité des protéines étudiées, seules Yap, le PDGFRβ et P-Her3 corrèlent avec la prolifération des cellules de schwannomes humain. De plus, Yap induit la transcription des RTK activés (à l’exception de Tie2). Nous plaçons donc Yap au centre des mécanismes de régulation de la croissance des schwannomes humains et proposons que son inhibition pourrait représenter une nouvelle et prometteuse stratégie thérapeutique pour réduire la croissance de ces tumeurs. Nous apportons une nouvelle lecture des fonctions de Merlin, qui, par une potentielle interaction directe avec Yap, inhibe spécifiquement sa translocation dans le noyau indépendamment d’une régulation par la densité cellulaire ou par la voie Hippo. Par ailleurs, Merlin ne semble pas essentiel à l’activation de la voie Hippo dans les cellules de Schwann soulignant une fonction nouvelle et inattendue de Merlin dans la régulation de Yap et de la voie Hippo. Enfin nous avons étudié le rôle d’AmotL1, un puissant partenaire de Merlin et membre de la voie Hippo, dans la migration et la progression des cancers du sein. Nous mettons en évidence une fonction antagoniste de Merlin et AmotL1 dans la promotion de ces mécanismes soulignant une autre fonction nouvelle de Merlin en tant que suppresseur de la progression de cancers non associés à NF2
Schwannomas are benign tumors arising from Schwann cell hyper-proliferation under NF2 bi-allelic inactivation. They appear in the context of a rare hereditary disease called Neurofibromatosis type 2 (NF2) or in sporadic cases. To this day, surgery and radiotherapy remain the only options to treat these patients, mainly due to the lack of therapeutical targets identified. The NF2 loss associated cellular phenotype is the loss of cell contact inhibition. Two main functions of Merlin, the NF2 product, have emerged in the last decade. The first was shown by our group and consists in the accumulation of tyrosine kinase receptors (RTK) at the plasma membrane in schwannomas. The second involves Merlin in the regulation of the Hippo signaling pathway. This pathway is activated by cell contact and inactivates a couple of transcription co-factors, Yap and Taz, then participating in cell contact inhibition of proliferation. However, the mechanisms by which Merlin inactivates Yap and Taz remain unknown. In our studies, we aimed to determine both the molecular signature of human schwannomas taking advantage of a large proteomic study, and the relative importance of Yap in the tumor suppressor function of Merlin. We could show both a specific activation of five RTKs : PDGFRβ, Her 3, Her2, Axl and Tie2 and a specific nuclear accumulation of Yap in human schwannoma. Among all the protein studied, Yap, PDGFRβ and P-Her3 are the only ones to correlate with the proliferation of human schwannoma cells. Furthermore, the activated RTK (excepted Tie2) are transcriptional targets of Yap. Hence, we found Yap as a pivotal regulator of schwannoma growth and proposed its inhibition as a new and promising therapeutical target to reduce human schwannoma growth. In addition, we show that Merlin specifically inhibits Yap nuclear translocation into the nucleus of Schwann cells by a direct interaction which is independent from the regulation by cell density and by the Hippo pathway. Moreover, Merlin expression seems not to be essential for Hippo activation in Schwann cells which brings a new and unexpected role of Merlin in Yap and Hippo regulation. In the end, we studied the role of AmotL1, a strong Hippo partner of Merlin in the migration and progression of breast cancer. We could show an antagonist function of Merlin and AmotL1 in the promotion of these mechanisms highlighting a new progression suppressor function of Merlin in cancer which are not linked to NF2 mutations

Neurofibromatosis type 2 is an autosomal dominant disease characterized by the formation of schwannomas and other peripheral neuropathies. The nf2 gene encodes the protein Schwannomin, or merlin. Schwannomin (Sch) is a membrane-cytoskeletal linking protein that suppresses cell proliferation at high cell density and modulates cell shape. Sch's tumor suppressive activity is regulated by its localization, conformation, and phosphorylation at serine 518 (S518). Sch's localization is dependent on binding the scaffold protein, paxillin. Phosphorylation of Sch at S518 regulates its conformation and tumor suppressor function. In a negative feedback loop, unphosphorylated Sch restricts cell proliferation downstream of Rac and p21-activated kinase (Pak), whereas Pak-induced phosphorylation inactivates Sch's ability to inhibit Pak and cell proliferation. Little is known about the function of the phosphorylated form of Sch, or the molecular mechanisms leading to its phosphorylation. Here we demonstrate that Sch-S518 phosphorylation is dependent on paxillin-binding and plasma membrane localization in SCs. Phosphorylation of Sch at the plasma membrane is mediated by Cdc42-Pak and results in altered SC morphology and polarity. Moreover, we have identified two extracellular stimuli that trigger Sch-S518 phosphorylation; these are neuregulin (NRG) and laminin, two potent activators of SC proliferation and myelination. NRG promotes Sch-S518 phosphorylation downstream of ErbB2/ErbB3 through PKA, whereas laminin-1 stimulation of β1 integrin promotes Pak- dependent phosphorylation of Sch-S518. Additionally, we find that Sch promotes process formation and elongation in primary and myelinating SCs, independent of Sch S518 phosphorylation. However, Sch phosphorylation was found to influence SC differentiation, as expression of an unphosphorylatable variant, Sch-S518A, facilitated SC myelination, whereas expression of a phospho-mimicking variant, Sch-S518D, reduced the SC's ability to myelinate. Together, these findings have identified receptor-mediated and paxillin-dependent pathways that regulate phosphorylation and inactivation of Sch's tumor suppressor function. Additionally, these results have elucidated novel normal functions for Sch during peripheral nerve development and myelination, and identify novel therapeutic targets for treatment of NF2 and other peripheral neuropathies.
Ph.D.
Department of Biomolecular Science
Burnett College of Biomedical Sciences
Biomolecular Sciences PhD

Neurofibromatosis type 2 (NF2) is an inherited, multiple tumour disease caused by loss of the tumour suppressor protein, Merlin. There are several tumours associated with NF2 including; ependymomas, meningiomas and schwannomas. Merlin loss can also occur sporadically in all of these tumours and is associated with upregulation of various growth factor receptors and their relevant signalling pathways. At present the only treatment options for NF2 are surgery or radiosurgery, both of which incur serious morbidity and are unable to prevent recurrence of tumours. Either new drug treatments, or re-profiling of other drugs already commercially available, are urgently needed to improve outcome for NF2 patients. Cellular prion protein (PrPC), encoded by PRNP gene, is involved in tumour development by altering proliferation, adhesion, and survival in some cancers via focal adhesion kinase (FAK) /Src/ NFκB, cyclin D1 and p53 -proteins. Our group previously showed a strong elevation of PRNP gene activity in schwannoma. I hypothesise that PrPC may contribute to schwannoma development. To study the role of PrPC in schwannoma development I have used the well-established in vitro model of schwannoma that comprises primary human Schwann and schwannoma cells. I show that PrPC is upregulated in schwannoma as well as in Merlin-deficient meningiomas and human malignant mesotheliomas. In schwannoma PrPC is released both via exosomes and by α-cleavage which forms biologically active N- and C-terminal portions of the protein. PrPC contributes to pathological proliferation, adhesion and survival of schwannoma cells by activating ERK1/2, PI3K/AKT, cyclin D1, FAK, p53 pathways via the 37/67kDa non-integrin laminin receptor (LR/37/67kDa) and CD44. Furthermore, schwannoma cells appear to be intrinsically drug-resistant due to upregulation of MDR1 protein p-glycoprotein (p-gp) expression. P-gp expression is dependent on PrPC thus, inhibiting PrPC may be a good potential new therapeutic option for schwannoma patients, either alone or in combination with Sorafenib and p-gp inhibitor Valspodar (PSC833). An inhibitor of LR/37/67kDa/PrP interaction, NSC47924, or Bortezomib, a proteasome/NFκB inhibitor which has been approved for the treatment of multiple myeloma, could also be of beneficial therapeutic effect and is something to investigate in future work. I conclude that PrPC is an interesting new therapeutic target through its involvement with schwannoma patholgenesis and resistance to drug treatments PrPC may prove to be a good therapeutic target in other NF2-related tumours like meningiomas and schwannomas.

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Bachelors
Burnett School of Biomedical Sciences
Molecular Biology & Microbiology