Enhanced phosphorylation of T153 in soluble tau is a defining biochemical feature of the A152T tau risk variant
| Autor: | Lillian M. Daughrity, John D. Fryer, Monica Castanedes-Casey, Nicole M. Avendano, Virginia Phillips, Casey Cook, Aishe Kurti, Rosa Rademakers, Leonard Petrucelli, Dah Eun Chloe Chung, Jimei Tong, Karen Jansen-West, Dennis W. Dickson, Michael DeTure, Kelly M. Hinkle, Yari Carlomagno, Mei Yue |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Somatic cell A152T Mice Transgenic tau Proteins Neuropathology Biology lcsh:RC346-429 Pathology and Forensic Medicine Progressive supranuclear palsy 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine In vivo mental disorders medicine Corticobasal degeneration Animals Humans Genetic Predisposition to Disease Gliosis Phosphorylation lcsh:Neurology. Diseases of the nervous system Aged Aged 80 and over Neurons Dementia with Lewy bodies Research Brain Neurodegenerative Diseases Middle Aged medicine.disease 3. Good health Cell biology Disease Models Animal Tauopathy 030104 developmental biology Solubility Female Neurology (clinical) Human medicine Risk factor 030217 neurology & neurosurgery |
| Zdroj: | Acta Neuropathologica Communications, Vol 7, Iss 1, Pp 1-13 (2019) Acta Neuropathologica Communications Acta neuropathologica communications |
| ISSN: | 2051-5960 |
| DOI: | 10.1186/s40478-019-0661-2 |
| Popis: | 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, TauA152T-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 TauA152T-AAV mice, which were absent the soluble fraction of TauP301L-AAV mice. Providing new insight into the role of A152T in modifying risk of tauopathy, as well as validating the TauA152T-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. Electronic supplementary material The online version of this article (10.1186/s40478-019-0661-2) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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