The Role of Tau Proteoforms in Health and Disease

Tau is a microtubule-associated binding protein in the nervous system that is known for its role in stabilizing microtubules throughout the nerve cell. It accumulates as β-sheet-rich aggregates and neurofibrillary tangles, leading to an array of different pathologies. Six splice variants of this protein, generated from the microtubule-associated protein tau (MAPT) gene, are expressed in the brain. Amongst these variants, 0N3R, is prominent during fetal development, while the rest, 0N4R, 1N3R, 1N4R, 2N3R, and 2N4R, are expressed in postnatal stages. Tau isoforms play their role separately or in combination with others to contribute to one or multiple neurodegenerative disorders and clinical syndromes. For instance, in Alzheimer's disease and a subset of frontotemporal lobar degeneration (FTLD)-MAPT (i.e., R406W and V337M), both 3R and 4R isoforms are involved; therefore, they are called 3R/4R mix tauopathies. On the other hand, 4R isoforms are aggregated in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and a majority of FTLD-MAPT and these diseases are called 4R tauopathies. Similarly, Pick's disease has an association with 3R tau isoforms and is thereby referred to as 3R tauopathy. Unlike 3R isoforms, the 4R variants have a faster rate of aggregation that accelerates the associated neurodegenerative mechanisms. Moreover, post-translational modifications of each isoform occur at a different rate and dictate their physiological and pathological attributes. The smallest tau isoform (0N3R) is highly phosphorylated in the fetal brain but does not lead to the generation of aggregates. On the other hand, proteoforms in the adult human brain undergo aggregation upon their phosphorylation and glycation. Expanding on this knowledge, this article aims to review the physiological and pathological roles of tau isoforms and their underlying mechanisms that result in neurological deficits. Physiological and pathological relevance of microtubule-associated protein tau (MAPT): Tau exists as six splice variants in the brain, each differing with respect to expression, post-translational modifications (PTMs), and aggregation kinetics. Physiologically, they are involved in the stabilization of microtubules that form the molecular highways for axonal transport. However, an imbalance in their expression and the associated PTMs leads to a disruption in their physiological function through the formation of neurofibrillary tangles that accumulate in various regions of the brain and contribute to several types of tauopathies.