Amyotrophic Lateral Sclerosis Proteomic Signature And Treatment With Mesenchymal Stem Cell-derived Extracellular Vesicles

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a lifetime risk of 1:400, primarily affecting upper and lower motor neurons. Unfortunately, there are only two drugs approved to treat ALS, which increase patient survival only by a few months. This highlights the urgent need for developments of new ALS modifying therapies, which have been hampered by high failure rate of new drug candidates during clinical trials. Stem cell therapy is one of the promising approaches that is in development for treating ALS. The beneficial effects of stem cell therapy rely on their paracrine signaling, suggesting extracellular vesicles (EVs) as possible non-cell based therapy. In particular, mesenchymal stem cells (MSCs) contribute to reparative process. To better translate and assess therapeutic potential of MSC-EVs, we combined state of the art induced pluripotent stem cell (iPSC) technologies to obtain patient-derived spinal low motor neurons and a comprehensive proteomic analysis to decipher the proteomic signature. To investigate the key molecular perturbations underlying disease pathology of ALS, a comprehensive proteomic analysis was performed showing mutation-specific and common ALS-specific changes. Mutation-specific effects in ALS motor neurons with hexanucleotide expansion in C9ORF72 exhibit dysregulation in proteins targeting to ER and cytoplasmic translation . In FUS-ALS motor neurons, iron ion homeostasis and cellular response to stress processes are affected. In ALS-TDP-43 motor neurons protein transport and localization are affected. Common ALS mechanisms such as mRNA splicing, proteasomal ubiquitin and mitochondrial associated processes are dysregulated. Furthermore, we demonstrated these underlying dysregulated mechanisms after treatment with MSC-EVs. More importantly, MSC-EV treatment can restore the protein expression levels impaired in ALS suggesting for future therapeutic potential for ALS. ### Competing Interest Statement The authors have declared no competing interest.