دورية أكاديمية
Simulations of active zone structure and function at mammalian NMJs predict that loss of calcium channels alone is not sufficient to replicate LEMS effects.
| العنوان: | Simulations of active zone structure and function at mammalian NMJs predict that loss of calcium channels alone is not sufficient to replicate LEMS effects. |
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| المؤلفون: | Ginebaugh SP; Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, United States., Badawi Y; Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, United States., Laghaei R; Biomedical Application Group, Pittsburgh Supercomputing Center, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States., Mersky G; Biomedical Application Group, Pittsburgh Supercomputing Center, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States., Wallace CJ; Biomedical Application Group, Pittsburgh Supercomputing Center, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States., Tarr TB; Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, United States., Kaufhold C; Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, United States., Reddel S; Department of Clinical Neurology, Concord Hospital, Sydney, New South Wales, Australia., Meriney SD; Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, United States. |
| المصدر: | Journal of neurophysiology [J Neurophysiol] 2023 May 01; Vol. 129 (5), pp. 1259-1277. Date of Electronic Publication: 2023 Apr 19. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 0375404 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1598 (Electronic) Linking ISSN: 00223077 NLM ISO Abbreviation: J Neurophysiol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Bethesda Md : American Physiological Society Original Publication: Washington [etc.] |
| مواضيع طبية MeSH: | Lambert-Eaton Myasthenic Syndrome*/pathology, Animals ; Humans ; Calcium Channels/metabolism ; Neuromuscular Junction/metabolism ; Neurons/metabolism ; Calcium Channels, Q-Type ; Synaptotagmins ; Mammals/metabolism |
| مستخلص: | Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune-mediated neuromuscular disease thought to be caused by autoantibodies against P/Q-type voltage-gated calcium channels (VGCCs), which attack and reduce the number of VGCCs within transmitter release sites (active zones; AZs) at the neuromuscular junction (NMJ), resulting in neuromuscular weakness. However, patients with LEMS also have antibodies to other neuronal proteins, and about 15% of patients with LEMS are seronegative for antibodies against VGCCs. We hypothesized that a reduction in the number of P/Q-type VGCCs alone is not sufficient to explain LEMS effects on transmitter release. Here, we used a computational model to study a variety of LEMS-mediated effects on AZ organization and transmitter release constrained by electron microscopic, pharmacological, immunohistochemical, voltage imaging, and electrophysiological observations. We show that models of healthy AZs can be modified to predict the transmitter release and short-term facilitation characteristics of LEMS and that in addition to a decrease in the number of AZ VGCCs, disruption in the organization of AZ proteins, a reduction in AZ number, a reduction in the amount of synaptotagmin, and the compensatory expression of L-type channels outside the remaining AZs are important contributors to LEMS-mediated effects on transmitter release. Furthermore, our models predict that antibody-mediated removal of synaptotagmin in combination with disruption in AZ organization alone could mimic LEMS effects without the removal of VGCCs (a seronegative model). Overall, our results suggest that LEMS pathophysiology may be caused by a collection of pathological alterations to AZs at the NMJ, rather than by a simple loss of VGCCs. NEW & NOTEWORTHY We used a computational model of the active zone (AZ) in the mammalian neuromuscular junction to investigate Lambert-Eaton myasthenic syndrome (LEMS) pathophysiology. This model suggests that disruptions in presynaptic active zone organization and protein content (particularly synaptotagmin), beyond the simple removal of presynaptic calcium channels, play an important role in LEMS pathophysiology. |
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| فهرسة مساهمة: | Keywords: Lambert-Eaton myasthenic syndrome; MCell modeling; active zone; neuromuscular junction |
| المشرفين على المادة: | 0 (Calcium Channels) 0 (Calcium Channels, Q-Type) 134193-27-4 (Synaptotagmins) |
| تواريخ الأحداث: | Date Created: 20230419 Date Completed: 20230519 Latest Revision: 20240502 |
| رمز التحديث: | 20240502 |
| مُعرف محوري في PubMed: | PMC10202491 |
| DOI: | 10.1152/jn.00404.2022 |
| PMID: | 37073966 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1522-1598 |
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| DOI: | 10.1152/jn.00404.2022 |