RESUMEN
Spinal muscular atrophy (SMA) is a devastating childhood disease primarily affecting lower motoneurons in the spinal cord. SMA is caused by the loss of functional survival of motoneuron (SMN) protein, leading to structural and functional alterations of the cytoskeleton in motoneurons and other cells. Loss of SMN results in impairments of microtubule architecture, but the underlying mechanisms are not completely understood. In this study, we mechanistically analyzed the effects of SMN deficiency on microtubules, demonstrating a reduced stability together with a reduction in alpha tubulin detyrosination. This was caused by increased levels of microtubule-associated protein 1B and tubulin tyrosine ligase, resulting in mitochondrial mislocalization in SMA. Our findings suggest that altered tubulin post-translational modifications and microtubule-associated proteins are involved in the pathomechanisms of SMA, such as an impaired axonal transport of mitochondria.
Asunto(s)
Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos/patología , Neuronas Motoras/patología , Atrofia Muscular Espinal/patología , Mutación , Péptido Sintasas/metabolismo , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Animales , Transporte Axonal , Transporte Biológico , Células Cultivadas , Humanos , Ratones , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/genética , Microtúbulos/metabolismo , Mitocondrias , Neuronas Motoras/metabolismo , Atrofia Muscular Espinal/etiología , Atrofia Muscular Espinal/metabolismo , Péptido Sintasas/genética , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Tubulina (Proteína)/metabolismo , Tirosina/metabolismoRESUMEN
Spinal muscular atrophy (SMA) is a rare neurodegenerative disease caused by the absence of survival motor neuron (SMN) protein. SMN loss results in impairments of the cytoskeleton, including microtubules and regulatory proteins. However, the contribution of microtubule-associated proteins (MAPs) to microtubule dysregulations in SMA is not fully understood. In this study, we investigated neuronal MAPs responsible for the microtubule stability and growth, including MAP1A, MAP2, MAP6, MAP7, EB1, and EB3 using an in vitro model of SMA. Decreased MAP2 and EB3 levels were found in SMN-deficient motor neuron-like cells, and EB3 protein level was also relevant to MAP1B. SMN loss leads to an increase in EB3 comet numbers at proximal neurites, indicating increased microtubule growth. Our findings suggest that SMN deficiency simultaneously causes dysregulations of several MAPs, contributing to the perturbations of microtubule dynamics in SMA.