Tau Seeding · Identification and validation of human proteins that control tau seeding in cell-based and in vivo models

Identification and validation of human proteins that control tau seeding in cell-based and in vivo models

A broad range of human diseases is known to be associated with aberrations in the process of proteins reaching or maintaining their functional three-dimensional structure or conformation. There are ~50 currently documented disorders with a multitude of symptoms that are associated with the misfolding (i.e. the loss of their functional conformation) of normally soluble, functional peptides that subsequently convert into intractable aggregates leading to disease onset. A group of neurodegenerative diseases known as tauopathies, including its most prevalent form Alzheimer’s disease (AD), are characterized by the misfolding and aggregation of the microtubule-associated protein tau. Although tau is natively unfolded and therefore has no fixed three-dimensional structure, under pathological conditions it forms well-ordered, periodic and β-sheet-rich aggregates, which are common to most neurological illnesses and are held responsible to drive disease progression through templated protein misfolding or ‘seeding’. Understanding the processes by which this protein transitions from a soluble, functional protein to pathogenic aggregates as well as how these initial aggregates are able to template and thereby propagate misfolding, are key to identifying the very fundamental disease mechanisms of this variety of dementias. While increasing evidence is emerging that tau pathology progression is based on seeding and spreading mechanisms reminiscent of prion protein pathology, an in-depth understanding of the cellular pathways and cofactors that drive disease progression is, however, still lacking. In this project, we set out to identify tau seeding modulators by undertaking systematic investigations in mammalian cells deleting every human gene via CRISPR genome editing, and observing which ones affect the aggregation of tau. We found the cellular machinery for degrading unnecessary or dysfunctional components, called autophagy, to be highly relevant. To complete the project, we are currently using human cells and an in vivo fruit fly model to mechanistically unravel the interplay between tau seeing and processes of the autophagy machinery. Genes identified to robustly influence the formation or degradation of tau aggregates could be targeted for AD therapy.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз