Relation entre la phosphorylation de Tau et la fragmentation de l'appareil de Golgi
Alzheimer’s disease (AD) is characterized by two neuropathological lesions, senile plaques composed of Abeta peptide and neurofibrillary tangles formed by hyperphosphorylated and aggregated Tau protein. Interestingly, in AD, a fragmentation of Golgi apparatus is noted at early stages of the disease. It was recently shown that the extracellular pool of Abeta peptide can induce a fragmentation of the Golgi. However, several studies indicated that hyperphosphorylated Tau could also contribute to this fragmentation. We therefore examined whether hyperphosphorylated Tau could induce a fragmentation of the Golgi by overexpressing it in HeLa cells. Our results revealed that a Tau mutant mimicking hyperphophosphorylation induced an earlier fragmentation of the Golgi than a non-phosphorylable Tau mutant. We previously demonstrated that Tau can be secreted in the extracellular space, the mutant mimicking hyperphosphorylation being the most secreted. We then examined whether extracellular Tau was able to induce a fragmentation of the Golgi as noted for extracellular Abeta. Interestingly, the mutant mimicking Tau hyperphosphorylation was the sole form of Tau that could induce a Golgi fragmentation when it was present in the medium. We then determine whether the induction of the fragmentation by extracellular hyperphosphorylated Tau was linked to its phosphorylation state and/or to its high amount in the medium. Our results indicate that the Golgi fragmentation induced by hyperphosphorylated Tau was caused by its high levels in the medium. We also investigated which domain of Tau was involved in the induction of the Golgi fragmentation. Our results revealed that the sequence of Tau responsible the Golgi fragmentation is located in its C-terminal where the repeated sequences (MTBD) involved in its association with microtubules are found. However, no alteration of the microtubules was noted in the HeLa overexpressing Tau indicating that the microtubules would not be involved in Tau-induced Golgi fragmentation. This supports the fact that extracellular not intracellular Tau is responsible for the fragmentation of the Golgi. Finally, by examining the trafficking of the VSVG protein, we showed that the Golgi remained functional upon the overexpression of Tau in HeLa cells. In conclusions, our results demonstrated that extracellular tau is the main pool of Tau responsible for its induction of the Golgi fragmentation. The link between extracellular Tau and the fragmentation of the Golgi remains to be elucidated. Knowing that the Golgi fragmentation could become detrimental to neurons, extracellular Tau could be a therapeutic target for AD.
Alzheimer Tauopathie Golgi fragmentation hyperphosphorylation Tauopathy Extracellular Tau