Fibrillation and molecular characteristics are coherent with clinical and pathological features of 4-repeat tauopathy caused by MAPT variant G273R
Year: 2020
Type: article
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.
Source: Neurobiology of Disease
Institutions: Linköping University, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, Emory University, University of Pennsylvania, Hong Kong University of Science and Technology, UK Dementia Research Institute, The University of Queensland
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: Emory University, Wellcome Trust, Göran Gustafssons Stiftelser, Alzheimer's Society, National Institute for Health and Care Research, University College London, Alzheimer’s Research UK, Vetenskapsrådet, University College London Hospitals NHS Foundation Trust, UK Dementia Research Institute, National Institutes of Health, Goizueta Business School, Emory University, Medical Research Council, National Institute on Aging
Awards: G2409549499, Protein aggregation diseases, G4183424045, G4315210197, BRAINEACv2: a resource for the interpretation of genetic variation in multiple regions of the adult human brain, Understanding the genes for Parkinson's disease, G6323016957, BRAINEACv2: a resource for the interpretation of genetic variation in multiple regions of the adult human brain, G6781161026, Emory Alzheimer's Disease Center, G9000227779, Protein Misfolding and Disease
OpenAlex ID: W3088253797