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

Author Sepulveda-Diaz, Julia Elisa Google Scholar
Naini, Seyedeh Maryam Alavi Google Scholar
Minh Bao Huynh Google Scholar
Ouidja, Mohand Ouidir Google Scholar
Yanicostas, Constantin Google Scholar
Chantepie, Sandrine Google Scholar
Villares, Joao Autor UNIFESP Google Scholar
Lamari, Foudil Google Scholar
Jospin, Estelle Google Scholar
van Kuppevelt, Toin H. Google Scholar
Mensah-Nyagan, Ayikoe Guy Google Scholar
Raisman-Vozari, Rita Google Scholar
Soussi-Yanicostas, Nadia Google Scholar
Papy-Garcia, Dulce Google Scholar
Institution Univ Paris Est
UPMC
Hop Robert Debre
Sorbonne Paris Cite
Universidade Federal de São Paulo (UNIFESP)
Grp Hosp Pitie Salpetriere
Radboud Univ Nijmegen
Univ Strasbourg
Abstract 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 P-301L mutation hTau P-301L, 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-kappa B 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 P-301L, 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.
Keywords HS3ST2/3OST2
heparan sulphates
Alzheimer's disease
tauopathy
3-O-sulphation
Zebrafish
Language English
Sponsor Association France Alzheimer & Maladies Apparentees
SATT Idf Innov
CONACyT, Mexico
French Ministry of Higher Education and Research
Institute de Recherche Servier
Grant number CONACyT, Mexico: 308978
Date 2015-05-01
Published in Brain. Oxford: Oxford Univ Press, v. 138, p. 1339-1354, 2015.
ISSN 0006-8950 (Sherpa/Romeo, impact factor)
Publisher Oxford Univ Press
Extent 1339-1354
Origin http://dx.doi.org/10.1093/brain/awv056
Access rights Closed access
Type Article
Web of Science ID WOS:000353834100028
URI http://repositorio.unifesp.br/handle/11600/39061

Show full item record




File

File Size Format View

There are no files associated with this item.

This item appears in the following Collection(s)

Search


Browse

Statistics

My Account