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Identification d'une forme phosphorylée de BDNF : un nouveau mécanisme de régulation de la plasticité synaptique et de la mémoire ?

Abstract : Brain-Derived Neurotrophic Factor (BDNF) is a protein that plays an essential role in the survival and differentiation of neurons, as well as in the induction and expression of synaptic plasticity (Deinhardt and Chao, 2014; Lu et al., 2005). BDNF is highly expressed during adulthood and the reduction of its expression is implicated in many neurodegenerative diseases and psychological disorders (Anastasia and Hempstead, 2014). Its action on synaptic plasticity is critical for the establishment of cognitive functions and for the establishment of memory (Bekinschtein et al., 2008; Egan et al., 2003).BDNF exists as two forms with opposite functions, or Yin and Yang effects (Lu et al., 2005). Indeed, BDNF is synthesized as a precursor molecule, proBDNF, which has negative effects "Yin". By binding to the p75NTR receptor, proBDNF promotes apoptosis, dendritic retraction and long-term depression. In contrast, the cleaved form, mature BDNF (mBDNF), binds preferentially to the TrkB receptor that activates the signaling pathways promoting cell survival, differentiation, and long-term potentiation. Thus, mBDNF has positive effects or "Yang". The cleavage of BDNF therefore plays a key role in regulating its functional balance towards one or the other pathway. It is believed that proBDNF is cleaved into mBDNF by furin in the Golgi network or by pro-protein convertase 1/3 in secretory vesicles (Mowla et al., 2001; Seidah et al., 1996). The remaining proBDNF that has not been cleaved in the cell can be secreted and rapidly cleaved by plasmin or matrix metalloproteases (MMP7) into the extracellular space (Lee et al., 2001).Having diametrically opposite roles, together, mature BDNF and proBDNF allow fine regulation of neuronal survival and differentiation and of their activity-dependent synaptic plasticity (Lu et al., 2014; Yang et al., 2014). Since BDNF has critical roles in neuronal functions, it is not surprising that its expression and action are extremely regulated in time and space. However, even if the enzymes processing BDNF are well known, the mechanisms regulating BDNF cleavage are not yet understood.Here we show a new mechanism for the regulation of BDNF maturation via phosphorylation which directly impacts the functional balance. Indeed, we show that phosphorylation of the S130 residue, located at the interface between the pro- and the mature domain, decreases the efficiency of BDNF cleavage by furin, thus regulating the balance between immature and mature forms. This phosphorylation at the S130 site is catalyzed by ectokinases FJX1 and FAM69B which are localized in the Golgi apparatus with BDNF. Furthermore, by using phospho-mutant knock-in transgenic mice, we show that the phosphorylation of BDNF, by promoting the proBDNF form, inhibits the long-term potentiation and decreases the plasticity dynamics of the dendritic spines after neuronal stimulation. These results suggest a novel regulatory pathway for BDNF functional balance and suggest a critical role for S130 phosphorylation in learning and memory processes.In parallel, the search for potential kinases of BDNF led us to identify an exoPKA, located in the Golgi and interacting directly with BDNF. This atypical exoPKA phosphorylates BDNF at serine S130 and regulates its maturation and therefore the balance between the pro- and mature forms of BDNF. This exoPKA is different from the cytosolic PKA which suggests the existence of a new mechanism of regulation of plasticity by PKA via BDNF. Finally, we are testing the role of exoPKA on the downregulation of synaptic plasticity via the regulation of BDNF cleavage. These results will allow to determine the existence of a dichotomous action of PKA on plasticity whether cytosolic or Golgi/secreted PKA is activated.
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Submitted on : Thursday, July 23, 2020 - 2:21:26 PM
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  • HAL Id : tel-02905463, version 1




Julie-Anne Rodier. Identification d'une forme phosphorylée de BDNF : un nouveau mécanisme de régulation de la plasticité synaptique et de la mémoire ?. Neurosciences [q-bio.NC]. Université Grenoble Alpes, 2018. Français. ⟨NNT : 2018GREAV015⟩. ⟨tel-02905463⟩



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