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The actual molecular weight (MW, k Da), and the apparent (App.) MW of each tau isoform on SDS-PAGE, are indicated on the Tau expression is developmentally regulated, such that in the adult human brain, all six isoforms of tau are expressed in the CNS, whereas in foetal brain, only the shortest tau isoform (0N3R) is expressed .
Differential splicing of exons 2 and 3 results in 2N tau isoforms being relatively under-represented in comparison to 0N and 1N tau such that 0N, 1N, and 2N tau comprise 37, 54 and 9% of total human CNS tau, respectively [The structure of tau is important for its normal functions.
The amino acid sequence of the longest human CNS tau isoform (2N4R, 441 amino acids) contains a low proportion of hydrophobic amino acids relative to other proteins, rendering tau an overall hydrophilic protein [).
The N-terminal acidic projection domain (amino acids 1–150) contains two distinct alternatively spliced N-terminal inserts.
Tau is well established as a microtubule-associated protein in neurons.
However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is accompanied by synaptic dysfunction and neural cell death in a range of neurodegenerative disorders, collectively referred to as tauopathies.
A key neuropathological characteristic common to these diseases is the presence in the brain of deposits of the microtubule-associated protein tau, in various morphologies, which is apparent many years before the onset of clinical symptoms .
Recent advances in our understanding of the multiple functions and different locations of tau inside and outside neurons have revealed novel insights into its importance in a diverse range of molecular pathways including cell signalling, synaptic plasticity, and regulation of genomic stability.
The present review describes the physiological and pathophysiological properties of tau and how these relate to its distribution and functions in neurons.
On binding to microtubules, the terminal regions of tau become separated and the N terminus of tau projects away from the microtubule surface ), and although this region of tau does not bind to microtubules directly, it is involved in regulating microtubule dynamics, influencing the attachment and/or spacing between microtubules and other cell components .
The specific functions of the N-terminal inserts in tau are not yet well established, although these sequences appear to influence the distribution of tau because 0N, 1N, and 2N tau isoforms each show distinct subcellular localisations in mouse brain .