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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\u2010derived motor neurons carrying\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    mutations, alongside spinal ventral horns from mice with pathogenic\n                    <jats:italic>C9orf72<\/jats:italic>\n                    \u2010mutations. This cross\u2010species 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\u2010based formulation of the active pharmaceutical ingredient GM1 ganglioside that improves its bioavailability. GM1 stabilized mitochondrial Ca\n                    <jats:sup>2<\/jats:sup>\n                    \u207a handling, improved energy metabolism, and alleviated ER stress, preventing protein aggregation and restoring cellular proteostasis and counteracted behavioral deficits in\n                    <jats:italic>C9orf72<\/jats:italic>\n                    and\n                    <jats:italic>SOD1\u2010G93A<\/jats:italic>\n                    mouse models. Together, these findings underscore the central, convergent role for cellular disruptions in ALS and position TLN as a promising therapeutic candidate.\n                  <\/jats:p>","DOI":"10.1002\/advs.202514128","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T10:52:34Z","timestamp":1767610354000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Engineered GM1 Intersects Between Mitochondrial and Synaptic Pathways to Ameliorate ALS Pathology"],"prefix":"10.1002","volume":"13","author":[{"given":"Federica","family":"Pilotto","sequence":"first","affiliation":[{"name":"Institut Neuromyog\u00e8ne, Pathophysiology and genetics of the neuron and muscle Inserm U1315 CNRS Universit\u00e9 Claude Bernard Lyon I  Lyon France"},{"name":"Department of Neurology Inselspital University Hospital  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristan Dellazizzo","family":"Toth","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine &amp; Rehabilitation University of Missouri  Columbia Missouri USA"},{"name":"NextGen Precision Health University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvano","family":"Bond","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine &amp; Rehabilitation University of Missouri  Columbia Missouri USA"},{"name":"NextGen Precision Health University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Department of Neurology Inselspital University Hospital  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rim","family":"Diab","sequence":"additional","affiliation":[{"name":"Department of Neurology Inselspital University Hospital  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Y. 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