RESUMEN
The regenerative capacity of the Central Nervous System (CNS) is a key factor implicated in the pathogenesis of neurodegenerative diseases. In the present study, the regenerative capacity of the CNS is considered using one of the markers of regeneration, Growth Associated Protein-43 (GAP-43) and its proteolytic fragment GAP-43-3 in the Experimental Autoimmune Encephalomyelitis (EAE) animal model of multiple sclerosis. The EAE on Wistar rats was characterized as an adequate model of multiple sclerosis, with typical clinical (pares and paralysis) and morphological (infiltration of spinal cord and deformation of motoneurons) disorders. Normally about 60% of GAP-43 is cleaved by m-calpain and stays in the form of GAP-43-3. During severe form of EAE up to 85% of GAP-43 can be found cleaved. We speculated that the cleavage of GAP-43 can play a crucial role for regenerative capacity of CNS during EAE development. Thus the distribution of GAP-43 and GAP-43-3 in the spinal cord was analyzed. The manifestation of clinical signs of EAE has been found to be in correlation with the levels of GAP-43 proteolysis both in the homogenate of the spinal cord and on the spinal cord slices. The immunoreactive staining enabled the observation of the accumulation of GAP-43-3 predominantly in microglial cells.
Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Proteína GAP-43/metabolismo , Microglía/metabolismo , Neuronas Motoras/metabolismo , Médula Espinal/metabolismo , Animales , Calpaína/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Proteína GAP-43/genética , Expresión Génica , Masculino , Microglía/patología , Neuronas Motoras/patología , Esclerosis Múltiple , Regeneración Nerviosa , Proteolisis , Ratas , Ratas Wistar , Médula Espinal/patología , Médula Espinal/fisiopatologíaRESUMEN
Calpains are calcium-activated neutral cysteine proteases, involved in the regulation of a number of physiological functions. Substrates of calpains include receptors, kinases, phosphatases, cytoskeleton and synaptosomal proteins. Some of them undergo complete degradation, though most of the substrates are subjected to limited proteolysis, which results in proteins having new properties. In the following review, we discuss involvement of calpains in the regulation of synapse structure and function. Namely, calpains participate in the regulation of synthesis, release and reuptake of neurotransmitters, modulation of receptors, stabilization or destabilization of the neuronal cytoskeleton. However, uncontrolled hyperactivation of calpains leads to dysregulation of these processes causing neuronal death.