Structural and toxic mechanism of amyloid aggregation: inhibiting and encouraging Alpha-Synuclein

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

Salta

Congreso; XXXIX Reunión Anual de la Sociedad Argentina de Biofísica, Workshop del Centro de Biología Estructural del Mercosur (CeBEM) y 3rd Latin American Protein Society Meeting; 2010

SAB, CeBEM, LAPSM

The misfolding of proteins into a toxic conformation is proposed to be at the molecular foundation of neurodegenerative disorders including Parkinson´s disease (PD). 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. 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. 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.