Electromagnetic Modulation of the ALS Transcriptome: Toward a Non-Drug Therapeutic Strategy

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease hallmarked by progressive loss of neuromuscular junctions, cortical and spinal motor neurons (MNs), resulting in muscle paralysis. MNs are particularly vulnerable due to their long axons and high metabolic demands. ALS pathology involves impaired RNA metabolism, protein aggregation, cytoskeletal defects affecting organelle trafficking, and mitochondrial dysfunction, ultimately leading to neurodegeneration. Current treatments only marginally extend survival, calling for alternative therapies. We recently reported beneficial effects of electromagnetic alternating field stimulation (ACMS) on axonal regeneration and organelle motility in ALS. Here, we used iPSC-derived spinal MNs from familial ALS patients with FUS mutations to optimize magnetic field parameters regarding frequency, amplitude and duration. Using compartmentalized neuron cultures, we also tested different magnetic field orientations relative to axons. Following ACMS, we assessed axonal organelle trafficking and the nuclear DNA damage response (DDR) by live-cell imaging. Untreated ALS neurons showed clear defects in both assays. Exposure to magnetic AC sine waves above a threshold amplitude of 7 mT, applied perpendicular to the axonal plane with an optimal low frequency of 25 Hz, led to a sustained boost of mitochondrial and lysosomal motility for over one week and rehabilitation of DDR. These phenotypic improvements correlated with global transcriptomic changes revealed by RNA-sequencing. These phenotypic improvements correlated with global transcriptomic changes revealed by RNA-sequencing. While untreated mutant and wild-type neurons displayed different gene expression profiles, ACMS converged them to a novel, harmonized transcriptional state across all lines. Further analysis of differentially expressed genes (DEGs) yielded a conceptual model in which ACMS activates extracellular matrix (ECM)-mediated cell adhesion and neurotransmitter receptor, ion channel and kinase signaling pathways, ultimately modulating gene transcription and, thereby, motor- and microtubule-associated proteins. This model provides a framework for follow-up studies to experimentally validate the underlying mechanisms and assess the therapeutic potential of ACMS as an alternative biophysical treatment modality for neurodegenerative diseases.