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Tauopathies

The tauopathies are a heterogeneous group of neurodegenerative diseases that share the presence of aberrant tau aggregates [69]. Tau is a microtubule-associated protein that binds to tubulin and works to stabilize microtubules and promote microtubule assembly [70]. The microtubule- associated protein tau gene (MAPT) is located in an atypical genomic region of chromosome 17 and produces six isoforms of the tau protein by alternative splicing of exons 2, 3, and 10 [71]. The interaction of tau with the microtubules occurs through three (3R) or four (4R) imperfect repeat sequences in the carboxyl terminal of the protein. One of these four domains is encoded by exon 10; hence, the alternative splicing of this exon determines the number of microtubulebinding domains. In the adult human brain, 3R and 4R tau are present in approximately equal quantities [72].

Several pathogenic mutations in MAPT have been associated with different clinical phenotypes. These mutations appear clustered between exons 9 and 13 of the gene and may be roughly divided into two categories, depending on the pathogenic mechanism involved: protein function mutations and splicing regulation mutations. The first group of mutations impairs the ability of tau to interact with microtubules or to promote microtubule assembly; the second corresponds to mutations located in exon 10 (with the exception of those occurring in codon 301) and in flanking intronic regions that affect the alternative splicing of this exon and consequently increase the 4R/3R tau ratio. 4R tau appears to aggregate more readily than 3R tau, thus overproduction of 4R tau may lead to an excess of free 4R and consequently promote tau aggregation [73].

The most frequent phenotype associated with MAPT mutations is frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). This is a familial disorder mainly characterized by behavioural and cognitive disturbances with progression to dementia followed by parkinsonism. The clinical spectrum associated with MAPT mutations is, however, extensive. The same mutation may cause different clinical expressions in different families and even within the same family. This is the case with the most frequent MAPT mutation, p.P301L, that has been associated with cases resembling Pick’s disease, corticobasal degeneration, and progressive supranuclear palsy [74, 75]. Whereas it can be clearly argued that FTDP-17 and PD-D are undoubtedly distinct entities, recent evidence implicating genetic variability in MAPT to lifetime risk for PD suggests that expression of this protein is a critical factor in PD, despite the general lack of tau pathology in this disease.

 
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