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

Alexander Sandberg,Helen Ling,Marla Gearing,Beth Dombroski,Laura Cantwell,Lea R'Bibo,Allan Levey,Gerard D Schellenberg,John Hardy,Nicholas Wood,Josefin Fernius,Sofie Nyström,Samuel Svensson,Stefan Thor,Per Hammarström,Tamas Revesz,Kin Y Mok

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.

Highlights

Microtubule-associated protein tau (MAPT), encoded by MAPT gene, is important for the formation and maintenance of microtubules (Weingarten et al, 1975)
Of the 361 exomes that were sequenced, the mean coverage is ~69× with ~98.7% covering at least 6×, & 96.0% about 15× and a rare non-synonymous mutation in MAPT was identified in a single patient with H1H1 haplotype
We found only one additional non-synonymous variant in the exons of MAPT, rs2258689, in this case

Summary

Introduction

Microtubule-associated protein tau (MAPT), encoded by MAPT gene, is important for the formation and maintenance of microtubules (Weingarten et al, 1975). ⁎⁎⁎ Correspondence to: Dr Kin Y MOK, UK Dementia Research Institute at UCL and UCL Queen Square ION Department of Neurodegenerative Disease, Wing 1.2 Cruciform Building, Gower Street, London WC1E 6AU, UK. Clinical presentation of frontotemporal dementia is associated with different genetic mutations (Database, A.F.M, 2019; Greaves and Rohrer, 2019). Such heterogeneity extends to the clinicopathological aspect. Confirmed PSP and CBD may have more than one clinical presentation (Williams et al, 2005). On the other hand the classic Ri chardson's syndrome and corticobasal syndrome are not always caused by respectively underlying PSP and CBD pathologies (Ling et al, 2010)

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