Tau and MAPT genetics in tauopathies and synucleinopathies

Abstract

MAPT encodes the microtubule-associated protein tau, which is the main component of neurofibrillary tangles (NFTs) and found in other protein aggregates. These aggregates are among the pathological hallmarks of primary tauopathies such as frontotemporal dementia (FTD). Abnormal tau can also be observed in secondary tauopathies such as Alzheimer's disease (AD) and synucleinopathies such as Parkinson's disease (PD). On top of pathological findings, genetic data also links MAPT to these disorders. MAPT variations are a cause or risk factors for many tauopathies and synucleinopathies and are associated with certain clinical and pathological features in affected individuals. In addition to clinical, pathological, and genetic overlap, evidence also suggests that tau and alpha-synuclein may interact on the molecular level, and thus might collaborate in the neurodegenerative process. Understanding the role of MAPT variations in tauopathies and synucleinopathies is therefore essential to elucidate the role of tau in the pathogenesis and phenotype of those disorders, and ultimately to develop targeted therapies. In this review, we describe the role of MAPT genetic variations in tauopathies and synucleinopathies, several genotype-phenotype and pathological features, and discuss their implications for the classification and treatment of those disorders.

Keywords: Genetic variation; MAPT; Neurodegenerative disorders; Synucleinopathies; Tauopathies.

Figure 1

Structure of the six tau isoforms expressed in the adult human brain Human MAPT is located on chromosome 17q21.31 and has two main haplotypes: H1 (direct orientation) and H2 (inverse orientation). The gene contains 15 exons, including exon 0, which encodes the 5’ untranslated region (UTR). Tau isoforms can have zero, one, or two amino-terminal inserts based on alternative splicing of exons 2 and 3 (0N, 1N, 2N; shown in blue), The insertion of exon 3 is dependent on the presence of exon 2. Tau isoforms can also include three or four microtubule-binding repeats, depending on splicing of exon 10 (3R or 4R; shown in orange). Exon 4A corresponds to the alternative exon located between exons 4 and 5, and is expressed outside of the brain. Exon 6 is also expressed outside the brain, while exon 8 insertion has not been reported in humans. Adapted from Refs and . References: ,,,,

Figure 2

MAPT mutations and associated clinical presentations in frontotemporal lobar degeneration The vast majority of reported mutations are in exons 9-13 and in the intronic region following exon 10. The most commonly reported presentations are bvFTD, PSP, and unspecified types of FTD. The mutations associated with a bvFTD and unspecified FTD presentation are well distributed among exons 9-13, while all but 3 mutations presenting with a PSP phenotype are within exon 10 and the intronic region following it. The four mutations associated with a CBS presentation are located in exons 10 and 13. The two mutations associated with PNFA are in exon 12 and 13 and the two SD-associated mutation are located in exons 1 and 10. All the intronic mutations are associated with either bvFTD or an unspecified FTD subtype. PSP was the other clinical presentation observed in intronic mutations. The three most commonly reported mutations are N279K, P301L, and IVS10+16. Exons in orange encode the microtubule-binding repeats, while exons in blue encode the amino-terminal inserts. References: ,,–,