Calcium Dysregulation in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the spinal cord and brain, and is characterized by progressive muscle weakness, paralysis, and eventually, respiratory failure. Approximately, 90-95% of ALS cases occur sporadically, with the remaining 5-10% being familial ALS, among which 20% exhibit mutations in the Cu, Zn superoxide dismutase (SOD1) protein. There is evidence that the dysregulation of Ca 2+ homeostasis in motor neurons plays a central role in ALS pathogenesis and may trigger other early signs of disease progression, namely Golgi fragmentation and mitochondrial dysfunction. The goals of our study were (i) to determine whether boosting the expression or activity of organellar Ca 2+ pumps (SPCA1, SPCA2 and SERCA) could offer protection against ALS pathogenesis and (ii) to determine the sequelae of cell phenotypes downstream of Ca 2+ dysregulation. Here, ALS cell models were established by transfecting mouse motor neuron-like NSC-34 cell lines with human hSOD1WT and mutant hSOD1G93A to investigate Ca 2+ dynamics, Golgi morphology, mitochondrial function and oxidative stress. NSC-34 cells expressing mutant hSOD1G93A demonstrated higher basal Ca 2+ levels, Golgi fragmentation, decreased mitochondrial membrane potential and greater susceptibility to oxidative stress compared to hSOD1WT control. Similar dysfunction could be elicited in hSOD1WT cells in response to bisphenol (SPCA1 inhibitor) or thapsigargin (SERCA inhibitor), which could be reversed by a cell permeable Ca 2+ chelator. Co-transfection with SPCA plasmids or treatment with a small molecule activator of SERCA conferred substantial protection against several pathological hallmarks of ALS. Similarly, in NSC-34 cells transfected with full length and nuclear localization signal truncated (ΔNLS) TDP-43 plasmids, co-transfection with SPCA1 reversed cytoplasmic mislocalization of TDP-43 in the mutant model. Overall, we suggest that restoration of calcium homeostasis may offer a novel therapeutic opportunity in the treatment of ALS and other neurodegenerative disorders. FVE Foundry This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.