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Accueil > Agenda > Les séminaires Jean Roche > Structure, function and manipulation of neuronal proteins.

Structure, function and manipulation of neuronal (...)

Horaire : 11 heures

Localisation : IFR Jean Roche de Neurosciences, Nouvelle salle de conférence rdc nord bât. E secteur Nord de la Faculté de Médecine, CS 80011, 51 bd. Pierre Dramard 13 344 Marseille cedex 15.

Téléphone - télécopie : 04 91 69 87 25 , courriel : ifr.jr


Introducing two ongoing projects : Structural basis of CNG channel gating and a therapeutic approach to Alzheimer’s disease

Dieter Willbold et al.

Institute of Complex Systems, ICS-6 : Structural Biochemistry, Research Centre, Jülich and Institut für Physikalische Biologie, Heinrich-Heine-Universität, Düsseldorf, Germany.

Ion channels activated by cyclic nucleotides are widely distributed throughout eukaryotes, play key roles in signal transduction of sensory neurons and neuronal excitability, and belong to two subfamilies : Cyclic nucleotide-gated (CNG) channels and hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels. Whereas HCN channels are activated by voltage and CNG channels are virtually voltage independent, both channels are activated by cyclic nucleotide binding (cAMP and cGMP) to an intracellular cyclic nucleotide binding domain (CNBD), which is connected to the transmembrane core. Ligand binding favours the open state in both channels, potentially owing to a conformational change in the CNBD, which may be conferred to the pore. The mechanistic details that underlie nucleotide activation of CNBDs are not fully understood. In order to elucidate the mechanism of channel opening, we have determined the solution structure of an isolated cyclic nucleotide binding domain of a CNG channel from Mesorhizobium loti which is homologous to eukaryotic CNBDs.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Several lines of evidence suggest a central role of amyloid-β-peptide (Aβ) in the pathogenesis of AD. More than Aβ fibrils, small soluble Aβ oligomers are suspected to be the major toxic species responsible for disease development and progression. In any case, agents that interfere with oligomer and fibril formation may be valuable for therapy or prevention of AD. The present study reports on in vitro and in vivo properties of the D-enantiomeric amino acid peptide "D3". We show that next to plaque load and inflammation reduction, oral application of the peptide improved cognitive performance of AD transgenic mice. In addition, we are providing in vitro data elucidating the potential mechanism underlying the observed in vivo activity of D3. These data suggest that D3 precipitates toxic Aβ species and converts them into non-amyloidogenic, non-fibrilar and non-toxic aggregates without increasing the concentration of monomeric Aβ. Thus, D3 is a therapeutically active substance exerting an interesting and novel mechanism of action.

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