ABSTRACT Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal condition marked by the degeneration of motor neurons. ALS has been linked to numerous genes with diverse biological roles, reflecting a highly intricate and multifaceted disease process. This diversity poses significant challenges in developing universally effective and bioavailable treatments. Advancing therapeutic strategies require uncovering molecular pathways that are major drivers of ALS. We conducted proteomic analyses of human iPSC‐derived motor neurons carrying C9ORF72 mutations, alongside spinal ventral horns from mice with pathogenic C9orf72 ‐mutations. This cross‐species approach revealed disruptions in synaptic vesicle release, endoplasmic reticulum (ER) and mitochondrial stress responses as conserved ALS pathogenic mechanisms. Disease progression was associated with accumulation of cytotoxic protein aggregates and oxidative stress. We analyzed the potential of GM1, an established neuroprotective molecule, to reverse these pathogenic features. To enhance the pharmacokinetics of GM1, we developed Talineuren (TLN), a nanoliposome‐based formulation of the active pharmaceutical ingredient GM1 ganglioside that improves its bioavailability. GM1 stabilized mitochondrial Ca 2 ⁺ handling, improved energy metabolism, and alleviated ER stress, preventing protein aggregation and restoring cellular proteostasis and counteracted behavioral deficits in C9orf72 and SOD1‐G93A mouse models. Together, these findings underscore the central, convergent role for cellular disruptions in ALS and position TLN as a promising therapeutic candidate.
Pilotto et al. (Mon,) studied this question.