Tau/MAPT disease-associated variant A152T alters tau function and toxicity via impaired retrograde axonal transport
| Autor: | Sandra E. Encalada, Biao Li, Edgar Gutierrez, Eva-Maria Mandelkow, Mihir Vohra, David Soriano-Castell, Aimee W. Kao, Frank J.A. Dennissen, Juan A. Oses-Prieto, Austin L Wang, Dominique A. Salazar, Miguel Alves-Ferreira, Sean D. Mooney, Victoria J. Butler, Kaveh Ashrafi, Alma L. Burlingame, Kathy H. Li, Beibei Jing, Alex Groisman |
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| Rok vydání: | 2019 |
| Předmět: |
pathology [Tauopathies]
Aging metabolism [Axons] Neurodegenerative medicine.disease_cause Alzheimer's Disease Axonal Transport Medical and Health Sciences Animals Genetically Modified Mice 2.1 Biological and endogenous factors etiology [Tauopathies] Phosphorylation Aetiology Genetics (clinical) Caenorhabditis elegans Genetics & Heredity 0303 health sciences Mutation 030305 genetics & heredity General Medicine Frontotemporal lobar degeneration Biological Sciences Cell biology Frontotemporal Dementia (FTD) Tauopathies Neurological Tauopathy Synaptic Vesicles Disease Susceptibility Protein Binding Tau protein Genetically Modified tau Proteins Biology 03 medical and health sciences ddc:570 mental disorders medicine Acquired Cognitive Impairment Genetics Animals Humans Molecular Biology metabolism [Synaptic Vesicles] Alleles Animal Neurosciences Genetic Variation Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) medicine.disease biology.organism_classification Axon initial segment metabolism [tau Proteins] Axons Brain Disorders Disease Models Animal genetics [tau Proteins] Amino Acid Substitution Disease Models Axoplasmic transport biology.protein Dementia metabolism [Tauopathies] |
| Zdroj: | Human molecular genetics, vol 28, iss 9 Human Molecular Genetics Human molecular genetics 28(9), 1498-1514 (2018). doi:10.1093/hmg/ddy442 |
| DOI: | 10.1093/hmg/ddy442 |
| Popis: | Mutations in the microtubule-associated protein tau (MAPT) underlie multiple neurodegenerative disorders, yet the pathophysiological mechanisms are unclear. A novel variant in MAPT resulting in an alanine to threonine substitution at position 152 (A152T tau) has recently been described as a significant risk factor for both frontotemporal lobar degeneration and Alzheimer's disease. Here we use complementary computational, biochemical, molecular, genetic and imaging approaches in Caenorhabditis elegans and mouse models to interrogate the effects of the A152T variant on tau function. In silico analysis suggests that a threonine at position 152 of tau confers a new phosphorylation site. This finding is borne out by mass spectrometric survey of A152T tau phosphorylation in C. elegans and mouse. Optical pulse-chase experiments of Dendra2-tau demonstrate that A152T tau and phosphomimetic A152E tau exhibit increased diffusion kinetics and the ability to traverse across the axon initial segment more efficiently than wild-type (WT) tau. A C. elegans model of tauopathy reveals that A152T and A152E tau confer patterns of developmental toxicity distinct from WT tau, likely due to differential effects on retrograde axonal transport. These data support a role for phosphorylation of the variant threonine in A152T tau toxicity and suggest a mechanism involving impaired retrograde axonal transport contributing to human neurodegenerative disease. |
| Databáze: | OpenAIRE |
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