Polymorphisms in the Tau Gene Increase the Risk of Neurodegeneration

A polymorphic intronic dinucleotide repeat in the tau gene has been linked to PSP (64). Indeed, the tau allele A0 is more frequently found in PSP patients than in healthy controls or AD patients (21). Two extended tau gene haplotypes that include the dinucleotide repeat polymorphism have been described. One of these haplotypes, H1, is significantly overrepresented in PSP patients (19,65-68). The functional consequences resulting from the presence of the H1 or the H2 haplotype remain controversial. Indeed, the haplotype block may also extend beyond the tau gene, so the involvement of polymorphisms in other genes cannot be ruled out.

Tau aggregation/hyperphosphorylation Decreased microtubule-bound tau Microtubule depolymerization Impaired axonal transport Stasis/aggregation of axonal traffic Synaptic dysfunction Axonal degeneration & disconnection

Microtubules f\ Jo

• -synuclein tau O vesicles

Tau aggregation/hyperphosphorylation Decreased microtubule-bound tau Microtubule depolymerization Impaired axonal transport Stasis/aggregation of axonal traffic Synaptic dysfunction Axonal degeneration & disconnection f\

Pathological aggregates

FIGURE 3 Deleterious effects of tau amyloidosis. Tau hyperphosphorylation and aggregation may lead to neuronal dysfunction through a variety of mechanisms, including microtubule depolymerization. This in turn may lead to impaired axonal transport, causing synaptic dysfunction and eventually axonal degeneration.

While the AO allele and H1 haplotype of tau were first associated with PSP, it quickly became apparent that they were also associated with CBD (19,65,69,70). Since PSP and CBD share biochemical, neuropathologic, and genetic overlap, these two diseases may ultimately represent different phenotypic manifestations of similar disease processes.

In addition to the association with CBD and PSP, the AO allele of tau shows a weak but significant overrepresentation in sporadic PD (71,72). Indeed, one of the regions giving the highest lod scores in genomic screens for PD is 17q21, the region that contains the tau gene, and multiple single-nucleotide polymorphisms in the tau gene are associated with sporadic PD (22). Furthermore, homozygosity for the tau H1 haplotype is associated with a ~57% increased risk of PD (73,74). The H1 haplotype may thus account for ~25% of the population attributable risk for PD (73). The association of tau genotype with PD must be reconciled with the apparent minor contribution of tau pathology to sporadic PD.

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