SIGNALING PATHWAYS REGULATING SYNAPTIC POTENTIATION TRIGGERED BY ALS-IgG IN MOTOR NERVE TERMINALS

M.R. PAGANI, R. REISIN & O.D. UCHITEL

Punta del Este, Uruguay

Simposio; ALS International Symposium; 2005

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuronal death. To date, there is no effective therapy and the patients usually die within 3 to 5 years after diagnosis. A ~10 % of the patients show an inherited form (familial ALS), whereas in a ~ 90 % of the patients the etiology is unknown (sporadic ALS). A variety of mechanisms, including excitotoxicity, oxidation-mediated damage, neurofilament aggregation and autoimmunity had been suggested in order to explain the pathogenesis of ALS. Observations made in research animals and ALS patients support the involvement of autoimmune mechanisms in sporadic ALS pathogenesis. Different clinical trials had been tested, with no improvement of the patients. A possible explanation may be that the diagnosis is obtained when the patients are seriously affected. In this way, the challenge of an earlier diagnosis and treatment arises. IgG from ALS patients (ALS-IgG) trigger synaptic potentiation at the neuromuscular transmission. Based on several observations we hypothesize that ALS-IgG-induced synaptic potentiation may be an early step of the motor neuronal degeneration in ALS. Thus, we investigated the significance of ALS-IgG, their molecular target localization and signaling mechanisms in ALS-IgG-induced synaptic potentiation at the neuromuscular synapses. This study showed that ALS-IgG induced a specific type of synaptic potentiation in neuromuscular synapses, mediated by the interaction with a molecular target localized at the motor nerve terminals. Moreover, the synaptic potentiation requires Ca2+ influx through Cav2.2 calcium channels and concomitant activation of a signaling pathway involving PLC, IP3 and ryanodine sensitive Ca2+ stores. As a result, this work supports the idea that ALS-IgG may be involved in motoneuron degeneration in ALS through specific signaling pathways.