Review articleTau and MAPT genetics in tauopathies and synucleinopathies
Section snippets
MAPT and tau: structure, function and interaction with alpha-synuclein
MAPT, located on chromosome 17q21.31, is composed of 15 exons and encodes the microtubule-associated protein tau. The gene has two main haplotypes due to a 900 kb inversion on chromosome 17q21 [10]. The H1 haplotype (direct orientation) is observed in all populations and has normal patterns of genetic variation, resulting in multiple different subhaplotypes [11]. The H2 haplotype (inverse orientation) is almost exclusive to individuals of European ancestry and has a prevalence of about 20% in
Frontotemporal dementia
FTD is a clinically and neuropathologically heterogeneous group of neurodegenerative disorders characterized by frontotemporal lobar degeneration (FTLD), executive dysfunction, behavioral abnormalities, personality changes, and progressive speech and language difficulties. Affected individuals might also develop motor symptoms such as parkinsonism with or without atypical features [[23], [24], [25], [26]]. The three main clinical subtypes of FTD are behavioral variant FTD (bvFTD), progressive
Synucleinopathies
Although this group of diseases is defined by the presence of alpha-synuclein accumulation, tau pathology is quite common, and a role for MAPT genetic variants has been demonstrated with different degrees of certainty.
Overlap between tauopathies and synucleinopathies
Tauopathies and synucleinopathies share various clinical, pathological, and genetic characteristics. Cognitive impairment is a feature of all the reviewed disorders (except MSA), and parkinsonism is also common in PD, DLB, MSA, PSP, and CBD. In fact, the four latter diseases are commonly considered as “Parkinson-plus” syndromes [187]. Parkinsonism can also be seen in FTD, CTE and late-stage AD (Table 1). Tau pathology may be present in all of these disorders, either as a primary or secondary
Discussion – the role of MAPT in the spectrum of neurodegeneration
The current review highlights the potential roles of MAPT variation and the tau protein in tauopathies and synucleinopathies. These diseases vary in terms of age of onset, clinical manifestations, pathology, and pattern of inheritance (Table 1). They also show some overlap. This overlap is even more prominent in FTD, PSP, and CBD, where the symptomatology of one disease can be associated with the pathology of another. In a recent study, 310 patients with a syndrome likely to be caused by
Concluding remarks
Despite the unclear mechanisms by which tau accumulation is associated with neurodegeneration, further understanding of the genetics MAPT is essential to improve disease classification and genotype-phenotype correlations of tauopathies and synucleinopathies. Furthermore, classification systems incorporating genetic information might better represent distinct pathogenic mechanisms and therefore better guide the development of new therapies and inclusion criteria in future clinical trials. In
Declaration of competing interest
ZGO Received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Inceptions Sciences (now Ventus), Ono Therapeutics, Denali, Handl Therapeutics, Neuron23 and Deerfield.
Acknowledgements
ZGO is supported by the Fonds de recherche du Québec–Santé Chercheur-Boursier award and is a Parkinson Canada New Investigator awardee. OAR is supported by the National Institutes of Health (NIH; R01 NS78086; U54 NS100693 and U54 NS110435), the US Department of Defense (W81XWH-17-1-0249), The Michael J. Fox Foundation, American Parkinson Disease Association (APDA) Center for Advanced Research, a Lewy Body Dementia Association Research Center of Excellence, the Mayo Clinic LBD Functional
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