L'Atrophie Musculaire spinale (SMA) est une maladie neurodégénérative causée par des mutations du gène SMN1 et caractérisée par la dégénérescence sélective des motoneurones alpha de la moelle épinière. les mécanismes moléculaires de la SMA ne sont aps clairs. cependant, deux hypothèses ont été retenues:D'une part, que la déficience en SMN entraine une perturbation de la biogenèse des snRNPs spliceosomales individuelles et par conséquent des défauts d'épissage. pendant ma thèse, nous avons montré que la déficience en SMN provoquait une diminution des particules tri-snRNPs majeures amis surtout mineures et que cela avait des conséquences sur l'épissage d'un sous-groupe de pré-ARNm contenant des introns mineurs.D'autre part, que la déficience en SMN entraine des altérations de transport d'ARN dans les axones, essentiels pour la survie des motoneurones. A part l'ARNm de la beta-actine et l'ARNm de cpg15 récemment identifié, ceux qui pourraient être transportés par SMN n'ont pas été décrits. nous avons donc identifié les ARN interagissant avec les isoformes a-SMN et SMN-fl dans des cellules neuronales, et montré que certains de ces ARN cibles colocalisent avec SMN dans les axones, suggérant qu'elle est impliquée dans leur transport. / Spinal Muscular Atrophy is a neurodegenerative disease caused by mutations in SMN1 gene. SMA is characterized by the loss of alpha-motoneurons of the spinal cord. However, the precise molecular mechanisms underlying the disease are still unkown. two hypotheses have been retained to explain SMA pathigenesis:In one hand, the fact that SMN deficiency leads to a perturbation of individual snRNPs biogenesis and consequently splicing defects. During my PhD, we have shown that SMN deficiency alters the levels of major, but mostly, minor tri-snRNPs. And that leads to splicing defects of a subset of pre-mRNA containing minor introns.In the other hand, that SMN deficiency causes alteration of axonal transport of RNAs crucial to motoneurons survival. Except beta-actin mRNA and the recently identified cpg mRNA, the RNA targets of SMN have not been described. We succeed to identify RNA targets of both a-SMN and SMN-fl isoformes in a neuronal cell line and colocalisation data of some of these targets suggested that SMN could be implicated in the transport of these RNAs.

京都大学 / 0048 / 新制・課程博士 / 博士(生命科学) / 甲第18483号 / 生博第312号 / 新制||生||41(附属図書館) / 31361 / 京都大学大学院生命科学研究科統合生命科学専攻 / (主査)教授 上村 匡, 教授 垣塚 彰, 教授 藤田 尚志 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

Final publication is available at http://www.sciencedirect.com/science/article/pii/S1873506115001191 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19579号 / 医博第4086号 / 新制||医||1013(附属図書館) / 32615 / 京都大学大学院医学研究科医学専攻 / (主査)教授 井上 治久, 教授 髙橋 良輔, 教授 岩田 想 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Although it is well-known that motor neuron disease (MND) primarily affects motor neurons, the involvement of sensory pathways in the disease is currently receiving more attention. There is a dearth of information regarding the atypical effects of MND, resulting in limited understanding of the vulnerability of for example the auditory system. The presence of hearing loss negatively impacts on participation across all communicative contexts, stripping individuals of autonomy and self-worth, ultimately resulting in withdrawal and isolation. These factors form the foundation for individual desire to pursue life-prolonging measures. Hearing loss, combined with dysarthria and the use of augmentative and alternative communicative strategies, implies that individuals with MND require additional support to meet their daily communicative needs. This descriptive, exploratory study aimed to identify the prevalence of hearing loss in eight individuals with adult onset MND. In addition, perceptions relating to the implications of auditory impairment and value of auditory diagnosis were explored. An evaluation of auditory function was performed on eight individuals with a neurologist confirmed diagnosis of MND. Auditory function was assessed using a comprehensive audiological test battery including both objective and subjective measures. Perceptions related to auditory impairment were determined using the Hearing Handicap Inventory for Adults (HHIA) and the Hearing Experience Questionnaire. Both individuals with MND and their primary caregivers completed the Hearing Experience Questionnaire. The results of the study indicate that a high frequency sensorineural hearing loss was identified in six participants. Auditory handicap, as measured by the Hearing Handicap Inventory for Adults, was reported in four participants, with social handicaps reported more than emotional handicaps. Individuals with MND and their caregivers identified communication as the most important functional skill. Interestingly, the caregivers related more to the threats auditory impairment than individuals with MND. The nature of hearing loss identified in this study mimics the pattern of a presbycustic (age-related) hearing loss. It is postulated that hearing loss may arise during disease course. Participants‘ limited understanding of the devastating consequences of hearing loss on quality of life highlights the need for inclusion of an audiologist as part of the multidisciplinary management team in MND. Audiological assessment, management, counseling and education will serve to guide the process of sensory regulation and limit psychosocial threats posed by MND. This will in turn promote enhanced quality of life and maintenance of individual autonomy.

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