Big tau: What, how, where and why

Over the last 50 years the different isoforms of tau proteins (45-60 kDa) have been a focus of research because of their roles in modulating the dynamic properties of microtubules shaping the structure and function of neurons but also becoming a center of attention in the pathology of neurodegeneration associated with tauopathies. Much less attention has been given to Big tau, a unique isoform containing exon 4a encoding about 250 amino acids to form a much longer projection domain of a protein of 110 kDa. Big tau is expressed in peripheral neurons and selective regions of the central nervous system in a defined transition during postnatal developmental stages. Although Big tau was discovered 30 years ago, there has been a persistent gap of knowledge regarding its physiological properties and pathological implications. This Perspective summarizes the progress so far in defining the structure and expression of Big tau within and outside the nervous system, proposes a role for Big tau in improving axonal transport in projecting axons, considers its potential in averting tau aggregation in tauopathies and highlights the need for further progress.