HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology
| Autor: | Minh Bao Huynh, Joao Villares, Nadia Soussi-Yanicostas, Rita Raisman-Vozari, Ayikoe Guy Mensah-Nyagan, Julia E. Sepulveda-Diaz, Sandrine Chantepie, Seyedeh Maryam Alavi Naini, Toin H. van Kuppevelt, Dulce Papy-Garcia, Constantin Yanicostas, Estelle Jospin, Foudil Lamari, Mohand Ouidir Ouidja |
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| Rok vydání: | 2015 |
| Předmět: |
p38 mitogen-activated protein kinases
tau Proteins Western blot Alzheimer Disease medicine Animals Humans Phosphorylation Protein kinase A GSK3B Cells Cultured Neurons medicine.diagnostic_test Behavior Animal Chemistry NF-kappa B Protein phosphatase 2 Original Articles medicine.disease Cell biology carbohydrates (lipids) Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10] Biochemistry Tauopathies Neurology (clinical) Tauopathy Sulfotransferases Intracellular |
| Zdroj: | Brain, 138, 1339-54 Brain, 138, Pt 5, pp. 1339-54 |
| ISSN: | 0006-8950 |
| DOI: | 10.1093/brain/awv056 |
| Popis: | Item does not contain fulltext Heparan sulphate (glucosamine) 3-O-sulphotransferase 2 (HS3ST2, also known as 3OST2) is an enzyme predominantly expressed in neurons wherein it generates rare 3-O-sulphated domains of unknown functions in heparan sulphates. In Alzheimer's disease, heparan sulphates accumulate at the intracellular level in disease neurons where they co-localize with the neurofibrillary pathology, while they persist at the neuronal cell membrane in normal brain. However, it is unknown whether HS3ST2 and its 3-O-sulphated heparan sulphate products are involved in the mechanisms leading to the abnormal phosphorylation of tau in Alzheimer's disease and related tauopathies. Here, we first measured the transcript levels of all human heparan sulphate sulphotransferases in hippocampus of Alzheimer's disease (n = 8; 76.8 +/- 3.5 years old) and found increased expression of HS3ST2 (P < 0.001) compared with control brain (n = 8; 67.8 +/- 2.9 years old). Then, to investigate whether the membrane-associated 3-O-sulphated heparan sulphates translocate to the intracellular level under pathological conditions, we used two cell models of tauopathy in neuro-differentiated SH-SY5Y cells: a tau mutation-dependent model in cells expressing human tau carrying the P301L mutation hTau(P301L), and a tau mutation-independent model in where tau hyperphosphorylation is induced by oxidative stress. Confocal microscopy, fluorescence resonance energy transfer, and western blot analyses showed that 3-O-sulphated heparan sulphates can be internalized into cells where they interact with tau, promoting its abnormal phosphorylation, but not that of p38 or NF-kappaB p65. We showed, in vitro, that the 3-O-sulphated heparan sulphates bind to tau, but not to GSK3B, protein kinase A or protein phosphatase 2, inducing its abnormal phosphorylation. Finally, we demonstrated in a zebrafish model of tauopathy expressing the hTau(P301L), that inhibiting hs3st2 (also known as 3ost2) expression results in a strong inhibition of the abnormally phosphorylated tau epitopes in brain and in spinal cord, leading to a complete recovery of motor neuronal axons length (n = 25; P < 0.005) and of the animal motor response to touching stimuli (n = 150; P < 0.005). Our findings indicate that HS3ST2 centrally participates to the molecular mechanisms leading the abnormal phosphorylation of tau. By interacting with tau at the intracellular level, the 3-O-sulphated heparan sulphates produced by HS3ST2 might act as molecular chaperones allowing the abnormal phosphorylation of tau. We propose HS3ST2 as a novel therapeutic target for Alzheimer's disease. |
| Databáze: | OpenAIRE |
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