SORL1 and its involvement in Alzheimer's disease pathogenesis and pathophysiology - Administrative Core

Columbia University Health Sciences, New York NY

Investigators

Abstract

ADMINSTRATIVE CORE SUMMARY/ABSTRACT While known for rare protein-truncation SORL1 variants, the pathogenesis and pathophysiology of the more common missense SORL1 variants remains unknown. As detailed in the Overview and throughout the application, this PPG sets out to address this problem. . The function of SORL1 most relevant to AD is its interaction with the retromer trafficking complex. Disruptions to SORL1-retromer and the trafficking pathway it serves is considered commonly pathogenic in late-onset (often called "sporadic, idiopathic") AD. Thus, better understanding of SORL1’s genetic loss-of-function will have broad translation impact. Even the potential therapeutic impact of the proposed studies promises to extend beyond the approximately 3% of patients harboring a SORL1 loss-of-function variant, to late-onset AD more generally. Achieving this goal requires a centralized effort that integrates and synergizes work by investigators spanning multiple levels of analysis. Accordingly, the PPG centralizes an international group of leading experts. Assembling a group of experts is one thing, assuring that they are socially and scientifically cohesive is another. The group of investigators that are part of this PPG all fulfill criteria as experts in their respective fields. The group has already been working together in regular meetings, in presenting together at scientific conferences, and in publishing together. The cohesion, therefore, already exists. Nevertheless, because so many levels of expertise are required for this PPG’s success, and while the assembled group of investigators have already been working together, it is undeniable that this PPG has many moving components. This Administrative Core will act as central command of this multi-dimensional and multi- component PPG. This core will oversee scientific progress, troubleshoot, manage a centralized budget, and interact with the NIH and other government agencies. Moreover, and perhaps more important for a PPG of this kind, the Administrative Core leaders will assure scientific and even social cohesion and integration.