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Scientific result | Highlight | Neurodegenerative diseases
In a new collaborative study published in Scientific Reports, researchers from the Gly-CRRET Laboratory (UPEC) and SEPIA (CEA-Jacob) deployed a novel cellular model to describe the induction of the autonomous abnormal aggregation of tau protein following the expression of HS3ST2, a sulfotransferase enzyme involved in heparan sulfates synthesis.
Neurodegenerative diseases are characterized by progressive neuronal deterioration leading to nervous system dysfunction and a gradual loss of cognitive and/or motor function.
A histological feature of these diseases is the development of cerebral lesions comprising accumulated intra or extracellular aggregates of faulty proteins upstream of neuronal degeneration.
Some of these protein clusters are specific to a single pathology whereas others are present in several. The microtubule protein tau is among these latter. Diseases sharing these abnormal deposits of tau are grouped under the term tauopathies. This group includes not only Alzheimer's disease but also frontotemporal dementias such as corticobasal degeneration and Pick's disease, among others. In pathological conditions, tau becomes hyperphosphorylated, which favors its aggregation, the formation of oligomers and finally structured clusters called neurofibrillary tangles.
Heparan sulfates (HSs) are polysaccharides normally present in cell membranes and the extracellular matrix. They have also been found associated with the amyloid and tau lesions in the neurons of patients with Alzheimer's disease. Indeed, studies performed in tauopathy cell and animal models have shown that specific forms of them, the 3-O-sulfated HSs (3S-HS; catalyzed in this context by 3-O-sulfotransferase-2 (HS3ST2)), are directly involved in the abnormal phosphorylation of the tau protein.
To continue this work and better understand the role of HSs in tauopathies, researchers from the Gly-CRRET laboratory (headed by Dr. Papy-Garcia) teamed with colleagues from SEPIA (Dr. Biard) to develop a new tauopathy cellular model built upon a genetic engineering approach and the use of replicative pEBV plasmids.
In their new model presented in Scientific Reports, the team demonstrated the induction of autonomous abnormal aggregation of wild-type (non-muted) tau. The team's new model stands out from others in that it does not require mutated tau and/or chemical or protein induction to set off the phenomenon of tau aggregation in cells.
The researchers deployed the pEBV episomes to stably express the tau protein in combination or not with the sulfotransferase enzyme HS3ST2 in the HEK293 cell line.
HS3ST2 is involved in the 3-O sulfation of heparan sulfates. In situ, it is only expressed in certain tauopathy-vulnerable neurons.
The team showed that heparan sulfates subjected to HS3ST2 sulfation (3S-HS) do not remain only in and outside of the cell membrane but migrate to the cell interior, where they encounter tau. The interaction between 3S-HS and tau results in the protein's abnormal phosphorylation and the production of tau oligomers.
These results are of interest particularly because they echo earlier studies describing the colocalization of abnormal heparan sulfates and hyperphosphorylated tau aggregates in the neurons of patients with Alzheimer's disease.
Having demonstrated the successful reproduction of a still poorly understood pathological phenomenon in a cell line easily manipulated by genetic engineering tools, this study may provide a path toward eased evaluations of novel pharmacological tools aimed at the interaction between heparan sulfates and the tau protein and ultimately the treatment of tauopathies.
HS3ST2 expression induces the cell autonomous aggregation of tau | Scientific Reports
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.