Charcot-Marie-Tooth disease (CMT) is the commonest inherited neuromuscular disorder, which affects the peripheral nervous system leading to nerve degeneration. CMT is categorised into two forms, ‘axonal’ and ‘demyelinating’, which reflects the main site of pathology as the axon or Schwann cells respectively. Over 90 genes have been identified associated with the disease. Among the genes associated with demyelinating CMT, the focus of my thesis is LITAF, mutations in which lead to an autosomal dominant demyelinating CMT known as CMT type 1C. LITAF is a 17 kDa protein likely to be involved in endocytic degradation and trafficking of specific cargo proteins. It contains an N-terminal proline-rich region mediating protein-protein interactions and a C-terminal LITAF domain consisting of a zinc-ribbon structure with a hydrophobic region incorporated. Most of the CMT1C mutations are clustered in this highly conserved LITAF domain. LITAF was predicted to play roles in recruiting ESCRT components and exosome formation, but the precise function remains unclear. Furthermore, why mutations in LITAF lead to CMT is not known. My work therefore focused on characterising the function of the LITAF protein both in health and disease. In my thesis, I first tried to determine the subcellular localisation of LITAF proteins and also investigated the function of the highly conserved C-terminal LITAF domain in targeting protein to the membrane. With regards to the function of LITAF, potential binding partners were screened using the traditional GST pull-down assay and the in-situ proximity labelling assay, BioID. A number of novel potential binding partners were identified in both assays. Among the list of potential binding partners, BAG3 was captured in both pull-down assays and was chosen for further studies. The interaction with LITAF was characterised and the potential role of this interaction in autophagy was investigated. Integrin, which was also captured in the BioID assay, was another protein chosen for further studies. Internalisation and recycling assay were developed to investigate the function of LITAF in integrin trafficking. The potential of CMT mutations in impairing the internalisation of integrin in A431 cells and the difficulty in performing the assays were discussed. Lastly, with patient fibroblasts available in our lab, disease phenotypes were analysed using two types of imaging technique: transmission electron microscopy (TEM) (in collaboration with J. Edgar) and immunofluorescence microscopy. Swollen vacuoles were observed in the TEM images of the patient fibroblasts only, and various uptake assays were performed to identify these enlarged compartments. In summary, this work offers an insight into the function of LITAF both in health and disease as well as identifying potential intracellular binding partners that might shed light on pathogenesis. Furthermore, the modified trafficking assays described in this thesis can be applied to Schwann cell and patient fibroblasts, providing further tools to probe the underlying membrane trafficking pathways that are dysfunctional in CMT.

Made available in DSpace on 2018-08-01T23:43:57Z (GMT). No. of bitstreams: 1 tese_9585_Dissertação final Flora Viguini do Amaral20161205-150640.pdf: 1488233 bytes, checksum: 4dd713171ad6b7c5b013054cf5f34c17 (MD5) Previous issue date: 2016-02-29 / O objetivo desta pesquisa é analisar o romance Borderline (2003), da escritora quebequense Marie-Sissi Labrèche, no campo da escrita de si, sob o prisma da autoficção, termo registrado pelo crítico e professor francês Serge Doubrovsky em Fils (1977). Este estudo visa averiguar, além da coincidência onomástica entre o nome da autora, da narradora e da personagem, a possibilidade de um jogo em que Labrèche cria um outro eu, capaz de fornecer supostas referências a traços autobiográficos mesclados a uma matéria ficcional. A pesquisa, portanto, consiste na investigação da relação entre o transtorno borderline e a estrutura do texto, examinando se o tema escolhe sua forma ideal de expressão, se a autora se faz valer dessa estrutura como sendo decisiva para inspirar a pensar esse transtorno psicológico. Ainda que a matriz teórica da autoficção seja francesa, não são muitas as publicações e trabalhos acadêmicos sobre esse efeito de leitura nas obras contemporâneas de autoras quebequenses. O corpus a ser analisado é Borderline. No que tange à teoria, serão utilizados os estudos acerca da perspectiva teórica da autoficção, por meio da contribuição de alguns teóricos, como Evando Nascimento e Leonor Arfuch. Palavras-chave: Autoficção. Borderline. Marie-Sissi Labrèche. Quebequense.

Notre intention, dans cette these, est d'examiner par une analyse interne le degre de coherence artistique qui existe aux niveaux symboliques, thematiques et structuraux dans Le Jour est noir de Marie-Claire Blais. A cette fin, nous nous servirons de trois methodes critiques: critique phenomenologique, critique thematique et critique structurale. Le premier chapitre etudie la symbolique du temps selon une methode phenomenologique. Dans le roman, les images qui se referent a l'eau constituent l'expression centrale du temps, formant un reseau temporel et spatial qui symbolise le passe, le present et l'avenir des person-nages. L'Eau est evoquee sous plusieurs aspects: la mer, la riviere, le brouillard et la neige. Leurs nuances symboliques seront examinees. Le deuxieme chapitre etudie la thematique de l'a-lienation. Deux niveaux d'alienation sont decrits: une alienation relative et une alienation absolue. Le troisieme chapitre examine la structure interieure du roman a la lumiere des observations de Claude Bremond sur la structure des oeuvres romanesques parues dans son article "La Logique des possibles narratifs." / Arts, Faculty of / French, Hispanic, and Italian Studies, Department of / Graduate

In the endless cycle of life and death, the issues of love and marriage are a constant and recurrent theme of literature. The man, as a foreigner, comes to court the woman with the intent of taking her away from her parents and bringing her into his own home. He must first convince the woman to leave the paternal location. The hearth, the center of the new home and the symbol of his wife, constitutes the one constant and stable aspect of the man's otherwise nomadic existence. The tensions and conflict inherent in this masculine struggle serve to mold and prepare the man for his future role as the protector and provider of his home and society. The woman, for her part, must also undergo -a spatial displacement. Not only must she travel to the new domicile, but she must also be prepared to change and adapt herself to the idea of leaving her birthplace. The vertical movement from the tower to the grove by way of the bedroom constitutes the process of maturation for the lady. Once she has proven herself capable of adulthood, the woman will assist her mate in gaining access to the society he had originally rejected in his search for self. Thus the woman serves as the instrument of God in redeeming the man while maintaining her own individuality, seen in the parallel process of displacement which she experiences. The reader response to the text of the Lais is based upon the realization that the reader also experiences a type of spatial displacement similar to that of the protagonists. Marie, through the use of a variety of literary mechanisms, forces the recipients of the text to go back in time and space to the mythic locale of Bretaigne. The purpose of this narrative technique is that, through identification with the various characters, each reader learns the proper methods of social interaction. In other words, the twelve stories form a manual of courtly etiquette. The Lens of Marie de France are not only for entertainment but for edification as well. / Arts, Faculty of / French, Hispanic, and Italian Studies, Department of / Graduate

Hereditary peripheral neuropathy, known asCharcot Marie Tooth disease (CMT) and with an incidence of 1:2500 -1:10 000, is the most common hereditary neuromuscular disorder. Type CMT 1A is the most common form of CMT refering to the group of primary demyelinitateing motor and sensory peripheral neuropathies. CMT phenotype is clinically characterized by chronic slowly progressive distal muscle weakness and atrophy with hypo or areflexia and mild to moderate acral sensory loss. The lower limbs are predominantly affected. The aims of this study were to describe the first and most common signs of CMT1A during the first decade of life, to characterize their progression, and evaluate the sensitivity of CMTNS (Charcot-Marie- Tooth neuropath scale) for CMT1A young children. Sixteen children aged 3 to 10 years with genetically proven CMT 1A were examined. All patients were clinically examined, underwent electrophysiological examination, and were scored by CMTNS. Eight were followed for up to two years. Our data shows that CMT 1A in children under the age of 10 years causes only a mild disability. Initial signs of CMT 1A were difficulty in heel walking (15/16, 93%) and lower limb hypo or areflexia ( 13/16, 81%). The test of heel walking can be easily used as a screening test for hereditary neuropathies in pediatrics....

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The lecture recital, given on April 18, 1983, began with biographical background that suggests the influences on the compositional development of both the composer, Charles Widor, and the poet, Paul Bourget, of the Chanons de mer. Songs were chosen to examine the characteristics that not only enhance Widor's poetic rendering, but impart to the Chansons de mer the more intellectual appeal often desired in today's concert repertoire.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.