Enhanced phosphorylation of T153 in soluble tau is a defining biochemical feature of the A152T tau risk variant
Year: 2019
Type: article
Abstract: Pathogenic mutations in the tau gene (microtubule associated protein tau, MAPT ) are linked to the onset of tauopathy, but the A152T variant is unique in acting as a risk factor for a range of disorders including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). In order to provide insight into the mechanism by which A152T modulates disease risk, we developed a novel mouse model utilizing somatic brain transgenesis with adeno-associated virus (AAV) to drive tau expression in vivo, and validated the model by confirming the distinct biochemical features of A152T tau in postmortem brain tissue from human carriers. Specifically, Tau A152T -AAV mice exhibited increased tau phosphorylation that unlike animals expressing the pathogenic P301L mutation remained localized to the soluble fraction. To investigate the possibility that the A152T variant might alter the phosphorylation state of tau on T152 or the neighboring T153 residue, we generated a novel antibody that revealed significant accumulation of soluble tau species that were hyperphosphorylated on T153 (pT153) in Tau A152T -AAV mice, which were absent the soluble fraction of Tau P301L -AAV mice. Providing new insight into the role of A152T in modifying risk of tauopathy, as well as validating the Tau A152T -AAV model, we demonstrate that the presence of soluble pT153-positive tau species in human postmortem brain tissue differentiates A152T carriers from noncarriers, independent of disease classification. These results implicate both phosphorylation of T153 and an altered solubility profile in the mechanism by which A152T modulates disease risk.
Authors: Yari Carlomagno, Dah-eun Chloe Chung, Mei Yue, Aishe Kurti, Nicole M. Avendano, Monica Castanedes-Casey, Kelly M. Hinkle, Karen Jansen-West, Lillian M. Daughrity, Jimei Tong, Virginia Phillips, Rosa Rademakers, Michael DeTure, John D. Fryer, Dennis W. Dickson, Leonard Petrucelli, Casey Cook
Institutions: Mayo Clinic, Mayo Clinic in Florida
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,290
Awards: The role of acetylation in regulating pathophysiology of tau, Manipulating tau's posttranslational modifications to block disease progression in vivo, G3299037761, G356518909, Capturing the molecular complexity of Alzheimer's disease through the lens of RNA binding proteins, Identifying genes and Pathways that impact Tau Toxicity in FTD, Genetic Discovery and Pathobiology of Frontotemporal Lobar Degeneration and Related TDP-43 Proteinopathies, Expanding insights into FTD disease mechanisms, G9000005508, Mayo Alzheimer's Disease Research Center
OpenAlex ID: W2913368128