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  • Review Article
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Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies

Nature Reviews Neurology volume 17, pages 601–620 (2021)Cite this article

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Abstract

Tauopathies are classified according to whether tau deposits predominantly contain tau isoforms with three or four repeats of the microtubule-binding domain. Those in which four-repeat (4R) tau predominates are known as 4R-tauopathies, and include progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathies and conditions associated with specific MAPT mutations. In these diseases, 4R-tau deposits are found in various cell types and anatomical regions of the brain and the conditions share pathological, pathophysiological and clinical characteristics. Despite being considered ‘prototype’ tauopathies and, therefore, ideal for studying neuroprotective agents, 4R-tauopathies are still severe and untreatable diseases for which no validated biomarkers exist. However, advances in research have addressed the issues of phenotypic overlap, early clinical diagnosis, pathophysiology and identification of biomarkers, setting a road map towards development of treatments. New clinical criteria have been developed and large cohorts with early disease are being followed up in prospective studies. New clinical trial readouts are emerging and biomarker research is focused on molecular pathways that have been identified. Lessons learned from failed trials of neuroprotective drugs are being used to design new trials. In this Review, we present an overview of the latest research in 4R-tauopathies, with a focus on progressive supranuclear palsy, and discuss how current evidence dictates ongoing and future research goals.

Key points

  • Several lines of evidence substantiate the concept that 4-repeat tauopathies form an aetiologically coherent disease continuum, including progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy and argyrophilic grain disease.

  • Neurobiological, neuroimaging and neuropathological data suggest that the spread of 4-repeat tau isoforms can induce neurodegeneration and propagation of tau pathology in a unifying disease mechanism.

  • 4-repeat tauopathies are increasingly recognized in clinical settings by their characteristic clinical manifestations, spanning from predominantly movement disorders and overlap syndromes to predominantly cognitive syndromes.

  • Biomarkers, such as tau PET ligands, are being developed to substantiate the diagnosis of 4-repeat tauopathies in living patients.

  • Currently, symptomatic therapeutic options for 4-repeat tauopathies are limited, but the available options must not be overlooked.

  • A broad spectrum of 4-repeat tau treatments are currently being developed, making the field of 4-repeat tauopathies an important testbed for precision medicine in neurodegenerative disorders.

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Fig. 1: Tau pathology and its distribution in 4R-tauopathies.
Fig. 2: Imaging characteristics of PSP–RS and CBS.
Fig. 3: PET findings in 4R-tauopathies.
Fig. 4: Targets of therapeutic interventions according to aetiopathogenetic cellular and molecular mechanisms in 4R-tauopathies.

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Acknowledgements

J.L.W. is supported by the National Institutes of Health (NIH) grants R01-NS89757, R01-DC12519 and R01-DC14942. G.G.K. is supported by the Rossy Foundation, “Rossy PSP Program”, the Edmond J. Safra Foundation and the Bishop Karl Golser Award. G.U.H. was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy; ID 390857198), DFG (HO2402/18-1), the German Federal Ministry of Education and Research (BMBF, 01KU1403A; 01EK1605A), the EU/EFPIA/Innovative Medicines Initiative [2] Joint Undertaking (IMPRIND grant 116060), the VolkswagenStiftung/Lower Saxony Ministry for Science/Petermax-Müller Foundation (Aetiology and Therapy of Synucleinopathies and Tauopathies).

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Authors and Affiliations

  1. Parkinson’s Disease and Movement Disorders Dept, HYGEIA Hospital, Athens, Greece

    Maria Stamelou & Nikolaos Giagkou

  2. European University of Cyprus, Nicosia, Cyprus

    Maria Stamelou

  3. Philipps University, Marburg, Germany

    Maria Stamelou

  4. Department of Neurology, Hanover Medical School, Hanover, Germany

    Gesine Respondek & Günter U. Höglinger

  5. Department of Radiology, Mayo Clinic, Rochester, MN, USA

    Jennifer L. Whitwell

  6. Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease (CRND), University of Toronto, Toronto, Ontario, Canada

    Gabor G. Kovacs

  7. Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada

    Gabor G. Kovacs

  8. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    Günter U. Höglinger

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Stamelou, M., Respondek, G., Giagkou, N. et al. Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies. Nat Rev Neurol 17, 601–620 (2021). https://doi.org/10.1038/s41582-021-00541-5

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