Electromagnetic modulation of the ALS transcriptome: towards a non-drug molecular cure

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease hallmarked by progressive loss of neuromuscular junctions and cortical and spinal motoneurons (MNs) yielding 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 field stimulations driven by alternating currents (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 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 rehabilitaiton of DDR. These phenotypic improvements correlated with global transcriptomic changes revealed by RNA-sequencing. While untreated mutant and wild-type neurons displayed distinct gene expression profiles, ACMS induced a novel, harmonized profile across all lines. Differential gene expression analysis suggests that ACMS activates extracellular matrix (ECM)-mediated cell adhesion and triggers neurotransmitter receptors, ion channels and kinase signaling pathways, ultimately altering gene transcription and, thereby, motor and microtubule-associated proteins. Our results highlight ACMS as a promising non-invasive, non-pharmacological treatment for neurodegenerative diseases.