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The Journal of Neuroscience, March 8, 2006, 26(10):2661-2672; doi:10.1523/JNEUROSCI.4394-05.2006

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Neurobiology of Disease
Calcium Signaling Pathways Mediating Synaptic Potentiation Triggered by Amyotrophic Lateral Sclerosis IgG in Motor Nerve Terminals

Mario R. Pagani,¹ Ricardo C. Reisin,² and Osvaldo D. Uchitel¹

¹Laboratorio de Fisiología y Biología Molecular, Instituto de Fisiología Biología Molecular y Neurociencias UBA-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina, and ²Servicio de Neurofisiología, Hospital Británico, C1280AEB Buenos Aires, Argentina

Correspondence should be addressed to Osvaldo D. Uchitel, Laboratorio de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II-2^do piso, C1428EHA Buenos Aires, Argentina. Email: odu{at}fbmc.fcen.uba.ar

Sporadic amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects particularly motoneurons. Several pieces of evidence suggested the involvement of autoimmune mechanisms mediated by antibodies in ALS. However, the significance of those antibodies in the disease and the underlying mechanisms are unknown. Here we showed that IgG purified from a group of sporadic ALS patients, but not familial ALS patients, specifically interact with the presynaptic membrane of motoneurons through an antigen–antibody interaction and modulated synaptic transmission. Immunoreactivity against nerve terminals showed strong correlation with synaptic modulation ability. In addition, several controls have ruled out the possibility for this synaptic modulation to be mediated through proteases or nonspecific effects. Effective IgG potentiated both spontaneous and asynchronous transmitter release. Application of pharmacological inhibitors suggested that activation of this increased release required a nonconstitutive Ca²⁺ influx through N-type (Ca_v2.2) channels and phospholipase C activity and that activation of IP₃ and ryanodine receptors were necessary to both activate and sustain the increased release. Consistent with the notion that ALS is heterogeneous disorder, our results reveal that, in 50% of ALS patients, motor nerve terminals constitutes a target for autoimmune response.

Key words: calcium channels; phospholipase C; IP₃R; RyR; calcium homeostasis alteration; signaling mechanisms

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Received June 24, 2005; revised Jan. 20, 2006; accepted Jan. 22, 2006.

Correspondence should be addressed to Osvaldo D. Uchitel, Laboratorio de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II-2^do piso, C1428EHA Buenos Aires, Argentina. Email: odu{at}fbmc.fcen.uba.ar

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				T. W. Gould, R. R. Buss, S. Vinsant, D. Prevette, W. Sun, C. M. Knudson, C. E. Milligan, and R. W. Oppenheim Complete Dissociation of Motor Neuron Death from Motor Dysfunction by Bax Deletion in a Mouse Model of ALS. J. Neurosci., August 23, 2006; 26(34): 8774 - 8786. [Abstract] [Full Text] [PDF]

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