Investigating the Nuclear Function of the C9orf72 Protein in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disorder where death of the upper and lower motor neurons causes progressive muscle wasting and paralysis. Currently, the approved treatments for ALS provide only a small therapeutic benefit to patients. A GGGGCC repeat expansion mutation that lies within the C9orf72 gene is causal of approximately 40% of the inherited form of ALS. The mutation has been demonstrated to cause haploinsufficiency of the C9orf72 protein and this loss of function is hypothesised to contribute to pathogenesis in C9orf72-ALS. Until recently, little was known about the protein function of C9orf72. We performed a yeast two-hybrid screen to investigate the C9orf72 interactome which identified binding between C9orf72 and coilin. Coilin is the major protein component of nuclear suborganelles, Cajal bodies, which are responsible for processing snRNPs that form the spliceosome. C9orf72-ALS patients exhibit splicing defects which correlate with disease severity. We therefore hypothesised that loss of the C9orf72-coilin interaction leads to dysregulation of Cajal bodies and splicing in C9orf72-ALS. The aims of this project were to characterise the C9orf72-coilin interaction and investigate the effect of C9orf72 on Cajal bodies and splicing. C9orf72 was found to interact with coilin directly in vitro and within cells, suggesting the interaction has biological importance. Depletion of C9orf72 in HEK293 cells led to an increase in the number of Cajal bodies, and a subtle defect in splicing. In contrast, C9orf72 overexpression decreased the number of Cajal bodies, but had little effect on splicing. Interestingly, investigation of Cajal bodies in C9orf72-ALS patient iAstrocytes found patients exhibited higher numbers of Cajal bodies in comparison to healthy controls. The work included in this thesis uncovered an interaction between C9orf72 and coilin and that depletion of C9orf72 can lead to abnormal numbers of Cajal bodies. The results support evidence for a novel, uncharacterised role for C9orf72 in the nucleus which may be linked with snRNP processing, Cajal bodies and splicing. Investigation into the function of nuclear C9orf72 will lead to greater understanding of the consequences of C9orf72 haploinsufficiency in ALS and may lead to development of better drug treatments for patients

Por el bien de la economía nacional: trabajo terapéutico y asistencia pública en el Manicomio de La Castañeda de la ciudad de México, 1929-1932 For the good of the nation's economy: therapeutic work and public assistance at La Castañeda asylum in Mexico City, 1929-32

El Manicomio de La Castañeda de la Ciudad de México, fundado en 1910, enfrentó hacia 1930 el problema de su masificación debido al elevado número de pacientes crónicos que hacían ver a la institución como un depósito de enfermos más que como un espacio terapéutico. Esta circunstancia condujo a la psiquiatría a su primera crisis de legitimidad como ciencia. Con el objetivo de combatir la leyenda negra en torno al manicomio, los médicos de La Castañeda promovieron la difusión en la prensa de un tratamiento de origen decimonónico que proyectaba la imagen pública de que los enfermos mentales podían tener la misma capacidad productiva que el resto de los hombres: la terapéutica por medio del trabajo. Esta propuesta contó con el apoyo del Estado emanado de la revolución mexicana porque el objetivo que guiaba la asistencia pública a los grupos más desprotegidos consistía en lograr su integración a la vida productiva del país a través del mercado, lo que se obtenía en el caso de los enfermos mentales a través de la terapia ocupacional.<br>Founded in 1910, by 1930 Mexico City's La Castañeda insane asylum was grappling with the problem of a massive number of chronic patients, a situation that earned it an image as a warehouse for the sick more than a place of treatment. Psychiatrists endeavored to restore the asylum's legitimacy by publicizing a nineteenth-century treatment which projected the public image that the mentally ill could be as productive as anyone else: work therapy. The government born of the Mexican revolution supported this proposal because the guiding objective behind public assistance for underprivileged groups was to make them part of the country's productive life via the market