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Simulations of active zone structure and function at mammalian NMJs predict that loss of calcium channels alone is
Scott P Ginebaugh1, Yomna Badawi1, Rozita Laghaei2
1Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Abstract:
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.
Insights
Lambert-Eaton myasthenic syndrome (LEMS) involves more than just reduced calcium channels. Computational models reveal that disrupted active zone organization and protein changes, like synaptotagmin loss, are key to LEMS.
Area of Science:
- Neuroscience
- Computational Biology
- Immunology
Background:
- Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder affecting the neuromuscular junction (NMJ).
- It is primarily linked to autoantibodies against P/Q-type voltage-gated calcium channels (VGCCs), reducing their number at active zones (AZs).
- However, some LEMS patients are seronegative for VGCC antibodies, suggesting other factors contribute to the disease.
Purpose of the Study:
- To investigate the complex pathophysiology of LEMS using a computational model of the NMJ active zone.
- To determine if reduced VGCCs alone sufficiently explain LEMS, or if other disruptions are involved.
- To explore potential mechanisms underlying seronegative LEMS.
Main Methods:
- Development and simulation of a computational model of the mammalian neuromuscular junction active zone.
- Integration of data from electron microscopy, pharmacology, immunohistochemistry, voltage imaging, and electrophysiology.
- Modification of the model to simulate various LEMS-related alterations.
Main Results:
- Models accurately predicted LEMS transmitter release and facilitation characteristics when incorporating multiple AZ disruptions.
- Key contributors to LEMS include decreased AZ VGCCs, impaired AZ protein organization, reduced AZ number, and synaptotagmin loss.
- Compensatory expression of L-type channels outside AZs was also noted.
- Models suggested that synaptotagmin loss and AZ disorganization alone could mimic LEMS, potentially explaining seronegative cases.
Conclusions:
- LEMS pathophysiology likely results from a combination of pathological alterations at the AZ, not solely VGCC loss.
- Disruptions in AZ organization and protein content, particularly synaptotagmin, are critical factors in LEMS.
- Computational modeling provides valuable insights into the complex mechanisms underlying LEMS and seronegative variants.
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