Toward the Discovery of Effective Polycyclic Inhibitors of Alpha-Synuclein Amyloid Assembly

LAMBERTO, G. R.; TORRES MONSERRAT, V.; BERTONCINI, C. W.; ZWECKSTETTER, M.; GRIESINGER, C.; FERNÁNDEZ, C.O.

Alta gracia, Córdoba

Congreso; Magnetic Resonance in a Cordubensis Perspective VI: New Development in NMR; 2011

The misfolding of proteins into a toxic conformation and their deposition as amyloid-like fibrils are proposed to be at the molecular foundation of neurodegenerative disorders including Creutzfeldt-Jakob´s, Alzheimer´s and Parkinson´s diseases (PD).1-3 A detailed understanding of the mechanism(s) by which proteins of wide structural diversity are transformed into morphologically similar aggregates is therefore of high clinical importance. Neurodegeneration in PD is progressive and characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of fibrillar cytoplasmatic aggregates of alpha-synuclein (AS) in multiple brain regions.4 Currently, no preventative therapy is available for PD and related synucleinopathies. Identification of therapeutic drugs is not only complicated by a lack of understanding of many of the key aspects of PD pathogenesis but also by the multifactorial etiology of the disease. The aggregation pathway of AS represents then one obvious target for therapeutic intervention in PD. Indeed, one approach to the development of therapeutic agents in neurodegenerative diseases has been the use of small molecules that specifically and efficiently inhibit the aggregation process.5-10 In this work we report high-resolution structural information of the interaction between AS and some of the most studied fibrillation inhibitors. The elucidation of the structural details of the interactions provided the basis for understanding the role of specific residues in the fibrillation pathway of AS and shed new light into the mechanistic basis that direct the inhibitory process of these anti-amyloidogenic compounds.     REFERENCES      1.   Chiti, F., and Dobson, C. M. Annu Rev Biochem, 2006, 75, 333.      2.   Luheshi, L. M., Crowther, D. C., and Dobson, C. M. Curr Opin Chem Biol, 2008, 12, 25.      3.   Sipe, J. D. Annu Rev Biochem, 1992, 61, 947.      4.   Spillantini, M. G., et al. Nature, 1997, 388, 839.      5.   Ehrnhoefer, D. E., et al. Nat Struct Mol Biol, 2008, 15, 566.      6.   Taniguchi, S., et al. J Biol Chem, 2005, 280, 7623.      7.   Chopra, V., et al. Proc Natl Acad Sci USA, 2007, 104, 16689.      8.   Caughey W. S., et al. Proc Natl Acad Sci USA, 1998, 95, 12122.      9.   Zhu, M., et al. J Biol Chem, 2004, 279, 26857.      10. Lee, E. N., et al. Biochemistry, 2004, 43, 3715.     ANPCyT, FUNDACIÓN ANTORCHAS, CONICET, MAX PLANCK SOCIETY, ALEXANDER VON HUMBOLDT FOUNDATION, IRB BARCELONA, FP7 MARIE CURIE IEF GRANT, AND DFG HEISENBERG SCHOLARSHIP