跳转至内容
Merck
  • HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology.

HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology.

Brain : a journal of neurology (2015-04-07)
Julia Elisa Sepulveda-Diaz, Seyedeh Maryam Alavi Naini, Minh Bao Huynh, Mohand Ouidir Ouidja, Constantin Yanicostas, Sandrine Chantepie, Joao Villares, Foudil Lamari, Estelle Jospin, Toin H van Kuppevelt, Ayikoe Guy Mensah-Nyagan, Rita Raisman-Vozari, Nadia Soussi-Yanicostas, Dulce Papy-Garcia
摘要

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-κB 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.

材料
货号
品牌
产品描述

Sigma-Aldrich
视黄酸, ≥98% (HPLC), powder
Sigma-Aldrich
氯化钠, for molecular biology, DNase, RNase, and protease, none detected, ≥99% (titration)
Sigma-Aldrich
氯化镁 溶液, for molecular biology, 1.00 M±0.01 M
Sigma-Aldrich
氯化镁, anhydrous, ≥98%
Sigma-Aldrich
氯化钠 溶液, 5 M in H2O, BioReagent, for molecular biology, suitable for cell culture
Sigma-Aldrich
氯化钠 溶液, 0.9% in water, BioXtra, suitable for cell culture
Sigma-Aldrich
氯化钠, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥99%
Sigma-Aldrich
氯化钠, BioXtra, ≥99.5% (AT)
SAFC
氯化钠 溶液, 5 M
Sigma-Aldrich
3,3′,5,5′-四甲基联苯胺, ≥99%
Sigma-Aldrich
氯化镁, powder, <200 μm
Sigma-Aldrich
氯化钠 溶液, BioUltra, for molecular biology, ~5 M in H2O
Sigma-Aldrich
氯化钠, BioUltra, for molecular biology, ≥99.5% (AT)
Sigma-Aldrich
氯化钠, 99.999% trace metals basis
Sigma-Aldrich
氯化钠 溶液, 5 M
Sigma-Aldrich
氯化镁 溶液, BioUltra, for molecular biology, 2 M in H2O
Sigma-Aldrich
3,3′,5,5′-四甲基联苯胺, ≥98% (TLC)
Sigma-Aldrich
氯化镁, BioReagent, suitable for insect cell culture, ≥97.0%
Sigma-Aldrich
氯化钠, meets analytical specification of Ph. Eur., BP, USP, 99.0-100.5%
Sigma-Aldrich
氯化镁 溶液, BioUltra, for molecular biology, ~1 M in H2O
Sigma-Aldrich
氯化镁 溶液, PCR Reagent, 25 mM MgCI2 solution for PCR
Sigma-Aldrich
3,3′,5,5′-四甲基联苯胺, ≥98.0% (NT)
Sigma-Aldrich
氯化镁, AnhydroBeads, −10 mesh, 99.9% trace metals basis
Sigma-Aldrich
氯化钠, BioPerformance Certified, ≥99% (titration), suitable for insect cell culture, suitable for plant cell culture
Sigma-Aldrich
3,3′,5,5′-四甲基联苯胺, tablet, 1 mg substrate per tablet
Sigma-Aldrich
氟化钠, BioReagent, suitable for insect cell culture, ≥99%
Sigma-Aldrich
氯化钠, AnhydroBeads, −10 mesh, 99.999% trace metals basis
Sigma-Aldrich
氯化钠-35Cl, 99 atom % 35Cl
Sigma-Aldrich
氯化钠 溶液, 0.85%
Sigma-Aldrich
氯化镁, AnhydroBeads, −10 mesh, 99.99% trace metals basis