We have developed multiple tools to study trans-cellular propagation. These have elucidated a fascinating biology of protein amyloids that likely plays a role in normal cell physiology. We have broken the pathogenic process down to its fundamental steps: cell binding, entry, replication/seeding, and release of seeds. We model each of these steps in a reductionist system.
We have previously identified a class of cell surface proteins, heparan sulfate proteoglycans (HSPGs), as the cell surface “receptors” for tau and synuclein aggregates. This discovery has immediately suggested new therapeutic strategies based on blocking tau binding to the cell surface, for which we have several drug development projects. HSPGs are extensively modified post-translationally. We are using genetic strategies to knock down the enzymes involved in this process to identify those that are required to facilitate tau uptake. We are using CRISPR-Cas9 screening to identify all genes required for uptake, intracellular seeding, and maintenance of tau aggregates. We anticipate that this will allow us to identify new drug targets to interfere with tau prion replication. This will also help us understand the biology of amyloids in a normal physiologic context.