Molecules in focus
Tau protein: Relevance to Parkinson's disease

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Abstract

Tau is a microtubule-associated protein linked with neurodegenerative diseases. Humans express six different isoforms of tau; the longest containing four microtubule-binding repeat motifs in the C-terminal that are vital for what is considered the major biological function of tau, to stabilize microtubules and facilitate axonal transport. The capacity of tau to maintain its normal biological function is dependent upon its phosphorylation state. In Alzheimer's and Parkinson's diseases, there is a hyperphosphorylation of tau that leads to the intracellular accumulation of tau in the form of neurofibrillary tangles. While the role of tau in Parkinson's disease has been understated for some time, here we summarize key genetic, pathological and biochemical evidence supporting a role for tau in the pathogenesis of Parkinson's disease. Toxic interactions with alpha synuclein may lead to hyperphosphorylation of tau and eventually to the deposition of both proteins in the disease.

Introduction

Tau protein is a member of the microtubule (MT) associated protein (MAP) family, which stabilizes and regulates MT assembly. The neuronal members of the MAP family includes large proteins (>200 kDa) such as MAP-2A and MAP-4, and smaller proteins such as tau and MAP-2C (Maccioni and Cambiazo, 1995), a number of which share a common 18 amino acid MT-binding repeat motif (Maccioni and Cambiazo, 1995).

Of the MAP family, tau has received particular attention owing to its links with neurodegenerative diseases. Tau is a major component of the neurofibrillary tangles (NFT) found in Alzheimer's disease (AD) (Hanger et al., 2009) and Parkinson's disease (PD) (Joachim et al., 1987, Bancher et al., 1993). The gene encoding tau, MAPT, has also been linked to frontotemporal dementia (FTD) and progressive supranuclear palsy (Lee et al., 2001) and more recently to PD (Tobin et al., 2008, Simon-Sanchez et al., 2009). The role of tau in AD and other diseases such as FTD has been extensively reviewed, but there has been little focus on the role of tau in the pathogenesis of PD, which will be the subject of this review.

Section snippets

Structure

Tau is encoded by a single gene located on chromosome 17q21, where 11 of the 16 exons are coding regions (Lee et al., 2001). mRNA splicing of exons 2, 3 and 10 generates 6 tau isoforms that differ by one or two short inserts in the N-terminal (0N, 1N, and 2N, respectively) and either three or four MT-binding repeat motifs in the C-terminal (3R and 4R-tau) (Fig. 1A). They consist of 352–441 amino acids (50–70 kDa).

Expression and activation

Fetal brain only expresses the shortest isoform of tau, while mature brain expresses all six isoforms (Spires-Jones et al., 2009). In the adult human brain, 3R/4R isoforms are equally expressed and it has been proposed that an altered 4R:3R tau ratio could destabilize MTs and lead to tauopathy (Lee et al., 2001).

The tau protein contains 85 potential phosphorylation sites in its longest isoform (Fig. 1B). Over 20 kinases have been found to phosphorylate tau, including proline-directed kinases

Normal biological function

Tau is found predominantly in neuronal cells, and was originally shown to be a regulator of tubulin assembly in vivo (Drubin and Kirschner, 1986). It has subsequently been demonstrated that the binding of tau to MT is dependent on the tau repeat region and its phosphorylation state. The strength of MT binding increases with the number of repeats in the tau MT-binding domain (Spires-Jones et al., 2009); while an increased phosphorylation state weakens MT-binding ability. For example,

Genetic linkage between tau and PD

There are two predominant MAPT haplotypes, H1 and H2, and the H1 haplotype is significantly associated with PD (Tobin et al., 2008, Edwards et al., 2010). The MAPT H1 subhaplotype with a ∼90-kb interval of the 5′ MAPT locus is preferentially associated with PD (Skipper et al., 2004). While the role of the H1 haplotype on disease pathogenesis is unknown, the H1 haplotype has been associated with increased tau expression in human brain (Simon-Sanchez et al., 2009). Taken together with recent

Conclusion

Tau is known as a key protein in various neurodegenerative diseases. Here we have summarized the genetic, pathological and biochemical evidence that supports the involvement of tau in PD, a previously underappreciated tau-related disease. Although compelling, it is presently unknown how tau contributes to PD, one possibility is that a pathological interaction between alpha synuclein and tau causes a toxic loss of function of axonal transport leading to deposition of toxic alpha synuclein and

Acknowledgements

Funded by the National Health and Medical Research Council of Australia, and the Australian Research Council.

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    Both authors contributed equally to this work.

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