Brain Transcriptome Analysis of a Protein-Truncating Mutation in Sortilin-Related Receptor 1 Associated With Early-Onset Familial Alzheimer's Disease Indicates Early Effects on Mitochondrial and Ribosome Function

Background: The early cellular stresses leading to Alzheimer's disease (AD) remain poorly understood 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 protein has been shown to act in the trafficking of the amyloid β A4 precursor protein (AβPP) that is proteolysed to form one of the pathological hallmarks of AD, amyloid-β (Aβ) peptide. However, other functions of SORL1 in AD are less well understood. Objective: To investigate the effects of heterozygosity for an EOfAD-like mutation in SORL1 on the brain transcriptome of young-adult mutation carriers using zebrafish as a model organism. Methods: We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1 and performed RNA-sequencing on mRNA isolated from the young adult brains of siblings in a family of fish either wild type (non-mutant) or heterozygous for the EOfAD-like mutation. Results: We identified subtle differences in gene expression indicating changes in mitochondrial and ribosomal function in the mutant fish. These changes appear to be independent of changes in mitochondrial content or the expression of AβPP-related proteins in zebrafish. Conclusion: These findings provided evidence supporting that EOfAD mutations in SORL1 affect mitochondrial and ribosomal function and provide the basis for future investigation elucidating the nature of these effects.