Retromer dysfunction at the nexus of tauopathies

Tauopathies define a broad range of neurodegenerative diseases that encompass pathological aggregation of the microtubule-associated protein tau. Although tau aggregation is a central feature of these diseases, their underlying pathobiology is remarkably heterogeneous at the molecular level. In this review, we summarize critical differences that account for this heterogeneity and contrast the physiological and pathological functions of tau. We focus on the recent understanding of its prion-like behavior that accounts for its spread in the brain. Moreover, we acknowledge the limited appreciation about how upstream cellular changes influence tauopathy. Dysfunction of the highly conserved endosomal trafficking complex retromer is found in numerous tauopathies such as Alzheimer's disease, Pick's disease, and progressive supranuclear palsy, and we discuss how this has emerged as a major contributor to various aspects of neurodegenerative diseases. In particular, we highlight recent investigations that have elucidated the contribution of retromer dysfunction to distinct measures of tauopathy such as tau hyperphosphorylation, aggregation, and impaired cognition and behavior. Finally, we discuss the potential benefit of targeting retromer for modifying disease burden and identify important considerations with such an approach moving toward clinical translation.