Propagation of tau pathology in the manner of prions has been hypothesized to underlie the progressive accumulation of tau aggregates in tauopathies. In experimental systems it has been easy to observe propagation of tau aggregation from the outside to the inside of the cell, and within brain networks in transgenic mice. However, it remains unknown whether this phenomenon is the cause of progressive neurodegeneration in human tauopathies. We do not know the molecular mechanisms by which tau aggregates taken into a cell can replicate unique structures. The identification of factors that are involved will help test the prion hypothesis of progressive neurodegeneration. Furthermore, understanding these mechanisms could help with the development of new therapies. We propose to use a newly developed tool to identify and characterize factors that are involved in tau aggregation. Ascorbate peroxidase (APEX2)-dependent proximity labeling is an enzymatic method for time-resolved biotinylation of proteins within a cell. We will identify peptides that have been labeled based on affinity purification and mass spectrometry. This will let us identify factors in close proximity to tau as the aggregation process begins, after macropinocytosis or direct delivery of aggregates to the cell interior. We will use standard genetics to follow up hits. This work could have strong impact on our understanding of the propagation of intracellular amyloids, and could form the basis for new therapeutic strategies.
Alzheimer's disease and related tauopathies are incurable neurodegenerative diseases that may progress because of propagation of tau aggregates from one cell to another, involving uptake and intracellular seeding. We propose to use a new method to label proteins in proximity to tau before, during, and after the intracellular aggregation process, and to study the effect of these proteins using genetic approaches. This work will help establish the pathological significance of transcellular propagation of aggregates, and might provide new therapeutic strategies for tauopathy.
