SORL1 and its involvement in Alzheimer's disease pathogenesis and pathophysiology - Core D: Variant Screening

Columbia University Health Sciences, New York NY

Investigators

Abstract

CORE D SUMMARY Alzheimer’s disease (AD) is poised to become the third leading cause of death in much of the developed world, and is the only major cause of death for which no preventive or disease-modifying treatment exists. If none is found, AD will cost the U.S. a trillion dollars annually by 2050. About 10% of all cases of AD are genetic and only 4 truly causal genes have been identified: APP, PSEN1, PSEN2, and SORL1. Of these, SORL1 is the only one that causes late onset AD that phenocopies the common sporadic disease. SORL1 encodes a huge, 2214- residue type I transmembrane protein that has at least 24 distinct domains. Its function in neurons is to help traffic cargo proteins to their correct destinations once they are endocytosed. To do this it forms a specific complex with cargo and with the retromer multiprotein assembly that is the master regulator of trafficking out of the early endosomes. Mutations in SORL1 either directly cause familial AD, are significant risk factors for the development of sporadic AD, or are relatively benign, depending on the variant. The effect of the pathogenic mutations seems to be to cause endosomal traffic jams, which ultimately lead to the degeneration of the neuron. Since pathogenic SORL1 mutations are involved in at least 2% of all AD cases, it is very important to be able to determine if a given mutation is pathogenic, and if the afflicted patient will be a candidate for therapy aimed at normalizing trafficking out of the endosome. The Program Project of which this Core is a component has as its goal the ability to validate SORL1 mutations for pathogenicity based on their effects on SORL1 structure, biochemical function, cell biology functions, and overall phenotypes. This pathogenicity assessment will guide future therapeutics being uniquely engineered for the restoration of SORL1 acticity, based on the specific underlying cellular mechanisms that will be uncovered during the proposed projects. Preliminary data from the researchers behind this Program Project has shown how pathogenic variants all result in decreased trafficking to the cell surface and production of a secreted fragment of SORL1, called sSORL1, which is a direct cause of impaired receptor recycling from the endosome to the neuronal cell surface. A unifying signature of pathogenic SORL1 variants is therefore likely decreased sSORL1 secretion. Core D will support the overall Program Project by screening the effects of 111 mutations in the SORL1 gene previously predicted to be pathogenic on the properties of receptor cell surface expressiona and sSORL1 cellular secretion, informing where on the pathogenic spectrum these variant locates framed by its effect on SORL1 trafficking. This information will be incorporated, along with cell biology, human genetics and mouse model data from the other Projects and Cores in the Program Project, to determine if the predicted genetic variants can be confirmed as pathogenic, and establish the parameters of SORL1 trafficking that distinguish pathogenic variants that leads to AD from non-pathogenic variants compatible with neuronal and endosomal fitness of the healthy aging brain.