Mechanisms of synaptic alteration mediated by antibodies from patients with amyotrophic lateral sclerosis
Background: Sporadic amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting 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 th...
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2007
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03250938_v32_n1_p9_Pagani http://hdl.handle.net/20.500.12110/paper_03250938_v32_n1_p9_Pagani |
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paper:paper_03250938_v32_n1_p9_Pagani2023-06-08T15:32:02Z Mechanisms of synaptic alteration mediated by antibodies from patients with amyotrophic lateral sclerosis Pagani, Mario Rafael Uchitel, Osvaldo Daniel Calcium channels Calcium homeostasis alteration IP3R Phospholipase C RyR Signaling mechanisms calcium channel immunoglobulin G phospholipase C ryanodine receptor amyotrophic lateral sclerosis article calcium homeostasis electrophysiology human immunohistochemistry immunoreactivity motor nerve nerve ending synaptic transmission Background: Sporadic amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting 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. Objectives: Examine the significance of those antibodies in the synaptic potentiation in motor nerve terminals. Methods: IgG were purified from a group of ALS patients and a group of control individuals. Electrophysiological and pharmacological tools as well as immunohistochemistry were used. Results and Conclusion: 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 (Cav2.2) 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. Fil:Pagani, M.R. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Uchitel, O.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2007 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03250938_v32_n1_p9_Pagani http://hdl.handle.net/20.500.12110/paper_03250938_v32_n1_p9_Pagani |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Calcium channels Calcium homeostasis alteration IP3R Phospholipase C RyR Signaling mechanisms calcium channel immunoglobulin G phospholipase C ryanodine receptor amyotrophic lateral sclerosis article calcium homeostasis electrophysiology human immunohistochemistry immunoreactivity motor nerve nerve ending synaptic transmission |
| spellingShingle |
Calcium channels Calcium homeostasis alteration IP3R Phospholipase C RyR Signaling mechanisms calcium channel immunoglobulin G phospholipase C ryanodine receptor amyotrophic lateral sclerosis article calcium homeostasis electrophysiology human immunohistochemistry immunoreactivity motor nerve nerve ending synaptic transmission Pagani, Mario Rafael Uchitel, Osvaldo Daniel Mechanisms of synaptic alteration mediated by antibodies from patients with amyotrophic lateral sclerosis |
| topic_facet |
Calcium channels Calcium homeostasis alteration IP3R Phospholipase C RyR Signaling mechanisms calcium channel immunoglobulin G phospholipase C ryanodine receptor amyotrophic lateral sclerosis article calcium homeostasis electrophysiology human immunohistochemistry immunoreactivity motor nerve nerve ending synaptic transmission |
| description |
Background: Sporadic amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting 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. Objectives: Examine the significance of those antibodies in the synaptic potentiation in motor nerve terminals. Methods: IgG were purified from a group of ALS patients and a group of control individuals. Electrophysiological and pharmacological tools as well as immunohistochemistry were used. Results and Conclusion: 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 (Cav2.2) 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. |
| author |
Pagani, Mario Rafael Uchitel, Osvaldo Daniel |
| author_facet |
Pagani, Mario Rafael Uchitel, Osvaldo Daniel |
| author_sort |
Pagani, Mario Rafael |
| title |
Mechanisms of synaptic alteration mediated by antibodies from patients with amyotrophic lateral sclerosis |
| title_short |
Mechanisms of synaptic alteration mediated by antibodies from patients with amyotrophic lateral sclerosis |
| title_full |
Mechanisms of synaptic alteration mediated by antibodies from patients with amyotrophic lateral sclerosis |
| title_fullStr |
Mechanisms of synaptic alteration mediated by antibodies from patients with amyotrophic lateral sclerosis |
| title_full_unstemmed |
Mechanisms of synaptic alteration mediated by antibodies from patients with amyotrophic lateral sclerosis |
| title_sort |
mechanisms of synaptic alteration mediated by antibodies from patients with amyotrophic lateral sclerosis |
| publishDate |
2007 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03250938_v32_n1_p9_Pagani http://hdl.handle.net/20.500.12110/paper_03250938_v32_n1_p9_Pagani |
| work_keys_str_mv |
AT paganimariorafael mechanismsofsynapticalterationmediatedbyantibodiesfrompatientswithamyotrophiclateralsclerosis AT uchitelosvaldodaniel mechanismsofsynapticalterationmediatedbyantibodiesfrompatientswithamyotrophiclateralsclerosis |
| _version_ |
1768544410863140864 |