Format

Send to

Choose Destination
Brain. 2015 May;138(Pt 5):1339-54. doi: 10.1093/brain/awv056. Epub 2015 Apr 4.

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

Author information

1
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.
2
3 INSERM UMR 1141, Hôpital Robert Debré, 75019 Paris, France 4 Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
3
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.
4
5 Aging and Neurodegenerative Diseases Brain Bank Investigation Laboratory, Universidade Federal de São Paulo, São Paulo, 04023-062, Brazil.
5
6 Biochimie des Maladies Neuro-métaboliques, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
6
7 Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
7
8 INSERM U1119, FMTS, Université de Strasbourg, 67000 Strasbourg, France.
8
2 Sorbonne Université UPMC UM75 INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
9
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.

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.

KEYWORDS:

3-O-sulphation; Alzheimer’s disease; HS3ST2/3OST2; Zebrafish; heparan sulphates; tauopathy

PMID:
25842390
PMCID:
PMC5963411
DOI:
10.1093/brain/awv056
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center