The molecular implications of a caspase-2-mediated site-specific tau cleavage in tauopathies

A major focus of current experimental therapies for neurodegenerative diseases is on modulating post-translational modifications(PTMs)of the microtubule-associated protein tau.Tau is a highly soluble,neuronal protein that is comprised of four domains–the N-terminal projection domain,the proline-rich region,the microtubule-binding domain,and the C-terminal tail.As a scaffold protein,tau dynamically interacts with numerous structural and functional biomolecules,such as cytoskeleton and motor proteins,chaperones,enzymes,DNA,RNA,and lipids.Over a dozen types of PTMs,combined with alternative splicing,confer upon tau its enormous structural heterogeneity,which subserves its many(patho-)physiological functions.