-Draft-
Web-Enabled Molecular Systems Architecture of Neuromuscular Junction
in Amyotrophic Lateral Sclerosis
Version 1.0. Last Updated: March 15, 2025
Supplementary Information To
A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis
V.A. Shiva Ayyadurai1,2, Prabhakar Deonikar1,2, and Roger D. Kamm31Systems Biology Group, CytoSolve Research Division, CytoSolve, Inc., Cambridge, MA2Open Science Institute, International Center for Integrative Systems, Cambridge, MA3Departments of Biological Engineering and Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA
Summary
This webpage provides the web-enabled molecular systems architecture of neuromuscular junction (NMJ) in amyotrophic lateral sclerosis as referred in the Discussion section of the publication (https://www.nature.com/articles/s41540-025-00501-5). The aim of this page is to provide an open source, web-enabled understanding of the NMJ “microenvironment” so the ALS community can provide feedback, be it new information, critiques, and comments to advance this understanding. The NMJ “microenvironment” herein differs from the more conventional view. The “conventional” ALS community for decades has viewed the NMJ “microenvironment” from a purely anatomical perspective to consist only of motor neurons, skeletal muscle cells, and the terminal Schwann cells. In contrast, in this paper and in the Supplementary Information, the “microenvironment” encompasses all cell types that interact with each other on a systems level. The NMJ microenvironment as described here is based on a systems-level perspective to include not only motor neurons, skeletal muscle cells, and terminal Schwann cells that reside anatomically in the immediate vicinity of the NMJs, but also those cells that impact total motor unit function from the NMJ to the brain, and therefore needs to include astrocytes, microglia, and oligodendrocytes, since they affect total motor unit function from the NMJ to the brain. This systems-level presentation of the NMJ microenvironment provides a more evolved understanding to advance ALS pathogenesis research.
The first diagram below provides a visual map that can be zoomed in and out of the entire molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis. Subsequent diagrams are modules of the main architecture in which the connecting lines can be clicked to find the references. The purpose of this page is to provide the ALS research community this open-sourced, web-enabled architecture from which they can provide continual feedback so this architecture may be updated and curated based on such feedback, to reflect the current understanding. Given this is a work in progress, the top of this page will denote the current version number, and link will be provided to release notes on any changes that were made to previous versions.
Table of Contents
Original Publication
Main Systems Architecture
NOX-ROS Signaling
Tweak-Fn14 Signaling
IL-6 Signaling
TGF-β Signaling
TDP-43 Signaling
SOD Signaling
Sema3a Signaling
SARM1 Signaling
Nrf2 Signaling
Nogo-A Signaling
mTOR Signaling
MMP-9 Signaling
Microglia Neuron Signaling
IL-1β Signaling
Glutamate Signaling
ER stress on ALS muscle Signaling
Endothelial Signaling
BMP Signaling
AMPA Signaling
Agrin-LRP4-MUSK Signaling
Ach Signaling
Feedback
Original Publication
Main Systems Architecture
