Elsevier

Parkinsonism & Related Disorders

Volume 90, September 2021, Pages 142-154
Parkinsonism & Related Disorders

Review article
Tau and MAPT genetics in tauopathies and synucleinopathies

https://doi.org/10.1016/j.parkreldis.2021.09.008Get rights and content

Highlights

  • MAPT encodes the microtubule associated protein tau.

  • Tau accumulates in disorders known as tauopathies, but also in other neurological diseases.

  • Rare and common genetic variants in MAPT may have different roles in these disorders.

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.

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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