Gonzalez-Velasco, O.; Parlato, R.; Yilmaz, R.; Decker, L.; Menge, S.; Freischmidt, A.; Yang, X.; Tulasi, N.; Brenner, D.; Andersen, P. M.; Forsberg, K.; Schlachetzki, J. C. M.; Brors, B.; von Voithenberg, L. V.; Weishaupt, J. H.

Several lines of evidence suggest that amyotrophic lateral sclerosis (ALS) pathology starts focally and spreads within the central nervous system (CNS). We leveraged DNA and RNA sequencing data from ALS autopsy tissue to explore the presence of somatic mosaic variants in sporadic ALS (sALS) cases. Deep targeted sequencing of known ALS disease genes from motor cortex tissue revealed enrichment of somatic variants in sALS compared to familial ALS (fALS) with a monogenic cause and an increased pathogenicity of mosaic mutations in known ALS mutational hot spots. Experimental validation of the variants identified that the somatic FUS variant p.E516X leads to nucleo-cytoplasmic mislocalization and aggregation. Additionally, somatic variant calling from single-cell RNA-sequencing data of sALS tissue showed an accumulation of somatic variants in excitatory neurons. Collectively, using a multi-modal approach, our findings suggest that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to the development of sALS.