The role of ER stress in the pathogenesis of Kennedy’s Disease

摘要: The fundamental function of the Endoplasmic Reticulum (ER) is to process nascent membrane and secretory proteins in a calcium-dependent manner. Disruption ER by depletion calcium results stress, which triggers apoptosis if prolonged. stress has been shown play role pathogenesis Motor Neuron Diseases (MNDs) CAG-repeat disorders. Kennedy’s Disease (KD) an X-linked neurodegenerative disease that classified as both MND disorder. In this Thesis I investigate whether Stress also plays KD. Using mouse model KD, primary motoneuron cultures from KD wild-type (WT) embryos were established. Confocal microscopy was used infer levels, markers stress-induced examined using western blot analysis immunocytochemistry. KD motoneurons found have reduced levels elevated relative WT controls. appears contribute death observed mice, since inhibition with Salubrinal increases Ca2+, decreases consequentially improves survival. Examination spinal cord mice revealed higher expression compared controls, most significant increase detected between E13 3 months age i.e. pre-symptomatically. Mitochondrial dysfunction impaired mitochondrial biogenesis motoneurons. However, increasing not effective improving viability. These show may early, causal suggest be potential therapeutic strategy for treatment KD.