A tangled web - tau and sporadic Parkinson's disease

Abstract

Parkinson's disease (PD) represents a major challenge for health care systems around the world: it is the most common degenerative movement disorder of old age, affecting over 100,000 people in the UK alone (Schrag et al., 2000). Despite the remarkable success of treatments directed at potentiating or replacing dopamine within the brain, which can relieve symptoms for over a decade, PD remains an incurable and invariably fatal disorder. As such, efforts to understand the processes that lead to cell death in the brains of patients with PD are a priority for neurodegenerative researchers. A great deal of progress has been made in this regard by taking advantage of advances in genetics, initially by the identification of genes responsible for rare Mendelian forms of PD (outlined in Table 1), and more recently by applying genome wide association studies (GWAS) to the sporadic form of the disease (Hardy et al., 2009). Several such GWAS have now been carried out, with a meta-analysis currently under way. Using over 6000 cases and 10,000 controls, two of these studies have identified variation at a number of loci as being associated with an increased risk of disease (Satake et al., 2009; Simon-Sanchez et al., 2009). Three genes stand out as candidates from these studies - the SNCA gene, coding for α-synuclein, the LRRK2 gene, coding for leucine rich repeat kinase 2, and MAPT, coding for the microtubule-associated protein tau. Mutations at all three of these loci have been associated with Mendelian forms of disease presenting with the clinical syndrome of Parkinsonism, however only SNCA and LRRK2 have been previously associated with pathologically defined PD (Hardy et al., 2009). Point mutations in α-synuclein, along with gene multiplication events, result in autosomal dominant PD, often with a significant dementia component. In addition to this, α-synuclein is the principle component of the main pathological hallmark of idiopathic PD, the Lewy body, making it an unsurprising hit in the GWAS (Spillantini et al., 1997). Mutations in LRRK2 are the most common genetic cause of PD, and so again made this gene a likely candidate as a susceptibility locus for the sporadic form of disease (Kumari and Tan, 2009). More surprising, perhaps, was the identification of tau as a susceptibility factor for Parkinson's. In this review we will outline the role of tau in neurodegeneration and in different forms of Parkinsonism, and speculate as to what the functional basis of the association between MAPT and PD might be. © 2010 Wray and Lewis.