title: HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology.
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 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.
authors.affiliation: 1 Laboratory Cell Growth, Tissue Repair and Regeneration (CRRET), Centre National de la Recherche Scientifique (CNRS) EA UPEC 4397/ERL CNRS 9215, Université Paris Est Créteil, Université Paris Est, F-94000, Créteil, France 2 Sorbonne Université UPMC UM75 INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Julia Elisa
authors.initials: JE
authors.lastname: Sepulveda-Diaz
authors.affiliation: 3 INSERM UMR 1141, Hôpital Robert Debré, 75019 Paris, France 4 Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Seyedeh Maryam
authors.initials: SM
authors.lastname: Alavi Naini
authors.affiliation: 1 Laboratory Cell Growth, Tissue Repair and Regeneration (CRRET), Centre National de la Recherche Scientifique (CNRS) EA UPEC 4397/ERL CNRS 9215, Université Paris Est Créteil, Université Paris Est, F-94000, Créteil, France.
authors.forename: Minh Bao
authors.initials: MB
authors.lastname: Huynh
authors.affiliation: 1 Laboratory Cell Growth, Tissue Repair and Regeneration (CRRET), Centre National de la Recherche Scientifique (CNRS) EA UPEC 4397/ERL CNRS 9215, Université Paris Est Créteil, Université Paris Est, F-94000, Créteil, France 2 Sorbonne Université UPMC UM75 INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Mohand Ouidir
authors.initials: MO
authors.lastname: Ouidja
authors.affiliation: 3 INSERM UMR 1141, Hôpital Robert Debré, 75019 Paris, France 4 Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Constantin
authors.initials: C
authors.lastname: Yanicostas
authors.affiliation: 1 Laboratory Cell Growth, Tissue Repair and Regeneration (CRRET), Centre National de la Recherche Scientifique (CNRS) EA UPEC 4397/ERL CNRS 9215, Université Paris Est Créteil, Université Paris Est, F-94000, Créteil, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chantepie
authors.affiliation: 5 Aging and Neurodegenerative Diseases Brain Bank Investigation Laboratory, Universidade Federal de São Paulo, São Paulo, 04023-062, Brazil.
authors.forename: Joao
authors.initials: J
authors.lastname: Villares
authors.affiliation: 6 Biochimie des Maladies Neuro-métaboliques, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Foudil
authors.initials: F
authors.lastname: Lamari
authors.affiliation: 1 Laboratory Cell Growth, Tissue Repair and Regeneration (CRRET), Centre National de la Recherche Scientifique (CNRS) EA UPEC 4397/ERL CNRS 9215, Université Paris Est Créteil, Université Paris Est, F-94000, Créteil, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Jospin
authors.affiliation: 7 Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: 8 INSERM U1119, FMTS, Université de Strasbourg, 67000 Strasbourg, France.
authors.forename: Ayikoe Guy
authors.initials: AG
authors.lastname: Mensah-Nyagan
authors.affiliation: 2 Sorbonne Université UPMC UM75 INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
authors.affiliation: 3 INSERM UMR 1141, Hôpital Robert Debré, 75019 Paris, France 4 Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Soussi-Yanicostas
authors.affiliation: 1 Laboratory Cell Growth, Tissue Repair and Regeneration (CRRET), Centre National de la Recherche Scientifique (CNRS) EA UPEC 4397/ERL CNRS 9215, Université Paris Est Créteil, Université Paris Est, F-94000, Créteil, France papy@u-pec.fr nadia.soussi@inserm.fr.
authors.forename: Dulce
authors.initials: D
authors.lastname: Papy-Garcia
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D015238:Sulfotransferases / Q000378:metabolism*; D024801:Tauopathies / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016328:NF-kappa B; D016875:tau Proteins; C485757:HS6ST2 protein, human; D015238:Sulfotransferases
keywords: 3-O-sulphation; Alzheimer’s disease; HS3ST2/3OST2; Zebrafish; heparan sulphates; tauopathy
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