TY  - JOUR
Y1  - 2020/12//
TI  - Fibrillation and molecular characteristics are coherent with clinical and pathological features of 4-repeat tauopathy caused by MAPT variant G273R
AV  - public
N2  - Microtubule Associated Protein Tau (MAPT) forms proteopathic aggregates in several diseases. The G273R tau mutant, 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.
UR  - https://doi.org/10.1016/j.nbd.2020.105079
ID  - discovery10110692
VL  - 146
N1  - © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
JF  - Neurobiology of Disease
A1  - Sandberg, A
A1  - Ling, H
A1  - Gearing, M
A1  - Dombroski, B
A1  - Cantwell, L
A1  - R'Bibo, L
A1  - Levey, A
A1  - Schellenberg, GD
A1  - Hardy, J
A1  - Wood, N
A1  - Fernius, J
A1  - Nyström, S
A1  - Svensson, S
A1  - Thor, S
A1  - Hammarström, P
A1  - Revesz, T
A1  - Mok, KY
KW  - 4-repeat tau
KW  -  Aggregation propensity
KW  -  CBD
KW  -  Corticobasal degeneration
KW  -  G273R
KW  -  MAPT
KW  -  PSP
KW  -  Pathology
KW  -  Progressive supranuclear palsy
KW  -  Tauopathy
ER  -