Familial Alzheimer's disease mutation identifies novel role of SORLA in release of neurotrophic exosomes.

INTRODUCTION: Mutations in SORL1, encoding the sorting receptor Sortilin-related receptor with A-type repeats (SORLA), are found in individuals with Alzheimer's disease (AD). We studied SORLA(N1358S), carrying a mutation in its ligand binding domain, to learn more about receptor functions relevant for human brain health. METHODS: We investigated consequences of SORLA(N1358S) expression in induced pluripotent stem cell (iPSC)-derived human neurons and microglia, using unbiased proteome screens and functional cell assays. RESULTS: We identified alterations in the SORLA(N1358S) interactome linked to biogenesis of exosomes. Consequently, the mutant receptor failed to promote release and neurotrophic qualities of exosomes, a defect attributed to altered exosomal content of microRNAs controlling neuronal maturation. DISCUSSION: We identified a role for SORLA in controlling quantity and neurotrophic quality of exosomes secreted by cells, suggesting impaired cellular cross talk through exosomes as a pathological trait contributing to AD pathology in carriers of SORL1 variants. HIGHLIGHTS: Familial Alzheimer's disease mutation in SORL1 changes interactome of mutant Sortilin-related receptor with A-type repeats (SORLA). Mutant SORLA impairs release of exosomes from neurons and microglia. Mutant exosomes lack neurotrophic qualities. Defect linked to alterations in microRNA content.