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

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dc.contributor.authorSepulveda-Diaz, Julia Elisa
dc.contributor.authorNaini, Seyedeh Maryam Alavi
dc.contributor.authorMinh Bao Huynh
dc.contributor.authorOuidja, Mohand Ouidir
dc.contributor.authorYanicostas, Constantin
dc.contributor.authorChantepie, Sandrine
dc.contributor.authorVillares, Joao [UNIFESP]
dc.contributor.authorLamari, Foudil
dc.contributor.authorJospin, Estelle
dc.contributor.authorvan Kuppevelt, Toin H.
dc.contributor.authorMensah-Nyagan, Ayikoe Guy
dc.contributor.authorRaisman-Vozari, Rita
dc.contributor.authorSoussi-Yanicostas, Nadia
dc.contributor.authorPapy-Garcia, Dulce
dc.contributor.institutionUniv Paris Est
dc.contributor.institutionUPMC
dc.contributor.institutionHop Robert Debre
dc.contributor.institutionSorbonne Paris Cite
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionGrp Hosp Pitie Salpetriere
dc.contributor.institutionRadboud Univ Nijmegen
dc.contributor.institutionUniv Strasbourg
dc.date.accessioned2016-01-24T14:40:28Z
dc.date.available2016-01-24T14:40:28Z
dc.date.issued2015-05-01
dc.description.abstractHeparan 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.en
dc.description.affiliationUniv Paris Est, CNRS, Lab Cell Growth Tissue Repair & Regenerat CRRET, UPEC,EA 4397,ERL 9215, F-94000 Creteil, France
dc.description.affiliationUPMC, Univ Paris 04, Inst Cerveau & Moelle Epiniere, CNRS,UMR 7225,INSERM,U1127,UM75, Paris, France
dc.description.affiliationHop Robert Debre, INSERM, UMR 1141, F-75019 Paris, France
dc.description.affiliationSorbonne Paris Cite, Univ Paris Diderot, Paris, France
dc.description.affiliationUniversidade Federal de São Paulo, Aging & Neurodegenerat Dis Brain Bank Invest Lab, BR-04023062 São Paulo, Brazil
dc.description.affiliationGrp Hosp Pitie Salpetriere, Biochim Malad Neurometab, F-75013 Paris, France
dc.description.affiliationRadboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, NL-6525 ED Nijmegen, Netherlands
dc.description.affiliationUniv Strasbourg, INSERM, U1119, FMTS, F-67000 Strasbourg, France
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Aging & Neurodegenerat Dis Brain Bank Invest Lab, BR-04023062 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipAssociation France Alzheimer & Maladies Apparentees
dc.description.sponsorshipSATT Idf Innov
dc.description.sponsorshipCONACyT, Mexico
dc.description.sponsorshipFrench Ministry of Higher Education and Research
dc.description.sponsorshipInstitute de Recherche Servier
dc.description.sponsorshipIDCONACyT, Mexico: 308978
dc.format.extent1339-1354
dc.identifierhttp://dx.doi.org/10.1093/brain/awv056
dc.identifier.citationBrain. Oxford: Oxford Univ Press, v. 138, p. 1339-1354, 2015.
dc.identifier.doi10.1093/brain/awv056
dc.identifier.issn0006-8950
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/39061
dc.identifier.wosWOS:000353834100028
dc.language.isoeng
dc.publisherOxford Univ Press
dc.relation.ispartofBrain
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://www.oxfordjournals.org/access_purchase/self-archiving_policyb.html
dc.subjectHS3ST2/3OST2en
dc.subjectheparan sulphatesen
dc.subjectAlzheimer's diseaseen
dc.subjecttauopathyen
dc.subject3-O-sulphationen
dc.subjectZebrafishen
dc.titleHS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathologyen
dc.typeinfo:eu-repo/semantics/article
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