SORL1 and its involvement in Alzheimer's disease pathogenesis and pathophysiology - OVERALL PROJECT SUMMARY/ABSTRACT SORL1 is emerging as only the 4th gene that is considered causal in Alzheimer’s disease. New insight shows how SORL1 functions by interacting with the retromer trafficking complex, how disrupting this interaction can mediate the disease’s cardinal pathologies, and how SORL1-retromer disruptions have been commonly linked to late-onset AD. The problem is that there are hundreds of disease-associated SORL1 variants, and the pathogenesis and pathophysiology of most of them remain unknown. The PPG’s overall goal is to solve this problem by relying on a recently developed prioritization framework designed to identify SORL1 missense variants most likely to be pathogenic. The framework uses the known effects of variants in proteins with similar domains to assess the likelihood that a SORL1 variant in a homologous domain may lead to a specific defect. As also detailed in the application, provisional support for this framework’s capabilities is provided by recent studies. The PPG’s overall approach is to rely on a unified set of SORL1 variants that the framework predicts to be pathogenic. The PPG’s Cores will provide biomaterials plus clinical and cellular evidence on the pathogenicity of each variant, using both standard and novel readouts. The Projects will collectively probe the pathophysiology of each of the pathogenic variants--- integrating structural, cellular, anatomical, and biofluidic investigations. The PPG’s Cores and Projects will have hypothesis-driven aims, building on existing evidence about how SORL1 loss-of-function variants affect the retromer-dependent endosomal recycling pathway, but they will also have unbiased aims designed to explore and expand the mechanistic understanding into how SORL1 might drive and/or modulate AD pathology. Collectively, by clarifying SORL1’s loss-of-function, the PPG promises to have high and broad translational impact. Ultimately, by completing the proposed studies, the PPG will inform on developing novel therapeutic interventions, not only for the estimated 3% of all AD patients who are thought to harbor a pathogenic SORL1 variant, but also for late-onset disease more generally.
