Fibrillation and molecular characteristics are coherent with clinical and pathological features of 4-repeat tauopathy caused by MAPT variant G273R

Neurobiol Dis. 2020 Dec;146:105079. doi: 10.1016/j.nbd.2020.105079.

Alexander Sandberg ¹, Helen Ling ², Marla Gearing ³, Beth Dombroski ⁴, Laura Cantwell ⁴, Lea R'Bibo ⁵, Allan Levey ⁶, Gerard D Schellenberg ⁷, John Hardy ⁸, Nicholas Wood ⁵, Josefin Fernius ¹, Sofie Nyström ¹, Samuel Svensson ⁹, Stefan Thor ¹⁰, Per Hammarström ¹¹, Tamas Revesz ¹², Kin Y Mok ¹³

Affiliations

1 Department of Physics Chemistry and Biology, Linköping University, Linköping, Sweden.
2 Queen Square Brain Bank for Neurological Disorders, Queen Square Institute of Neurology, University College London, London, UK.
3 Department of Pathology and Laboratory Medicine, Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology and Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.
4 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5 Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, University College London, London, UK.
6 Department of Neurology and Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.
7 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
8 UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, SAR, China.
9 Department of Physics Chemistry and Biology, Linköping University, Linköping, Sweden; CBD Solutions, Stockholm, Sweden.
10 School of Biomedical Sciences, The University of Queensland, Brisbane, Qld 4072, Australia.
11 Department of Physics Chemistry and Biology, Linköping University, Linköping, Sweden. Electronic address: [email protected].
12 Queen Square Brain Bank for Neurological Disorders, Queen Square Institute of Neurology, University College London, London, UK. Electronic address: [email protected].
13 UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK; Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, SAR, China. Electronic address: [email protected].

PMID: 32961270 DOI: 10.1016/j.nbd.2020.105079

Abstract

Microtubule Associated Protein Tau (MAPT) forms proteopathic aggregates in several diseases. The G273R tau mutation, located in the first repeat region, was found by exome sequencing in a patient who presented with dementia and parkinsonism. We herein return to pathological examination which demonstrated tau immunoreactivity in neurons and glia consistent of mixed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) features. To rationalize the pathological findings, we used molecular biophysics to characterize the mutation in more detail in vitro and in Drosophila. The G273R mutation increases the aggregation propensity of 4-repeat (4R) tau and alters the tau binding affinity towards microtubules (MTs) and F-actin. Tau aggregates in PSP and CBD are predominantly 4R tau. Our data suggest that the G273R mutation induces a shift in pool of 4R tau by lower F-actin affinity, alters the conformation of MT bound 4R tau, while increasing chaperoning of 3R tau by binding stronger to F-actin. The mutation augmented fibrillation of 4R tau initiation in vitro and in glial cells in Drosophila and showed preferential seeding of 4R tau in vitro suggestively causing a late onset 4R tauopathy reminiscent of PSP and CBD.

Keywords

4-repeat tau; Aggregation propensity; CBD; Corticobasal degeneration; G273R; MAPT; PSP; Pathology; Progressive supranuclear palsy; Tauopathy.

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