(The) role of somatic brain mutations in the onset of sporadic amyotrophic lateral sclerosis

Abstract

The aetiology in most sporadic cases of the fatal neurodegenerative disorder amyotrophic lateral sclerosis (sALS) remains unknown, despite multiple genetic factors having been identified successfully in familial cases (fALS). TARDBP gene being one of these most commonly observed, its protein product TDP-43 can be observed in its aggregated, phosphorylated form (pTDP-43) in up to 97% of all sALS cases. Using here a matched sampling approach, in which motor neurons (MNs) were gathered based on their pTDP-43 aggregation status through a selective laser capture microdissection (LCM) protocol and subsequently sequenced by WGS alongside peripheral organ tissue from the same individual, we sought to identify a genomic sALS cause in the form of somatic single nucleotide variants (sSNVs) at a clonal level. Numbers of sSNVs were significantly greater in sALS MNs than observed in neurotypical controls, and showed a somatic single base substitution (SBS) signature relating to DNA damage by oxidative stress. pTDP-43-aggregated MNs also harboured higher sSNV counts when compared to pTDP-43- neurons collected from the same patient in two cases. This increase in sSNVs compared to neurotypical individuals was isolated only to clonal variants of less than 0.2 variant allele frequency (VAF), whilst the oxidative stress signature observed was absent in significantly clonally expanded variants (>0.2 VAF). Findings here suggest that sALS can be predisposed to at a late stage of neurodevelopment, and that this predisposition is linked to an increase in oxidative stress and DNA damage acquired prior to MN maturation.