Transcriptome analysis of a protein-truncating mutation in sortilin-related receptor 1 (sorl1) associated with early-onset familial Alzheimer's disease indicates effects on mitochondrial and ribosome function in young-adult zebrafish brains

The early cellular stresses which eventually lead to Alzheimer's disease (AD) remain poorly understood. This is because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic late-onset AD (LOAD). SORL1 has been shown to play a role in the trafficking of the amyloid ß A4 precursor protein (APP) which is cleaved proteolytically to form one of the pathological hallmarks of AD, amyloid ß (Aß) peptide. However, the other functions of SORL1 are less well understood. Here, we employed a reverse genetics approach to characterise the effect of an EOfAD mutation in SORL1 using zebrafish as a model organism. We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1, and performed RNA-sequencing on mRNA isolated from a family of fish either heterozygous for the EOfAD-like mutation or their wild type siblings and identified subtle effects on the expression of genes likely indicating changes in mitochondrial and ribosomal function. Overall design: a total of 12 fish were used in this study: 6 wild-type samples and 6 sorl1 W1818*/+ samples (EOfAD-like). These fish arised from the same parents and were raised together in the same tank until 6 months of age.