title: Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations.
abstract: Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes α-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of α-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of α-synuclein toxicity. We critically assess the potential of experimental therapies targeting α-synuclein, and discuss steps that need to be taken for target validation and drug development.
authors.affiliation: Institute of Neurodegenerative Diseases, University of Bordeaux, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dehay
authors.affiliation: Institute of Neurodegenerative Diseases, University of Bordeaux, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bourdenx
authors.affiliation: Research Unit of Theoretical & Applied Economics, University of Bordeaux, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5113, 33608 Pessac, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gorry
authors.affiliation: Departments of Neurology, Pathology and Cell Biology, and the Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
authors.affiliation: Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas, 08035 Barcelona, Spain.|Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08193 Bellaterra, Barcelona, Spain.|Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Vila
authors.affiliation: ICM, Paris, France; Sorbonne Universités.|UPMC Université Paris 06, UM 75, ICM, Paris, France.|CNRS, UMR 7225, ICM, Paris, France.|Inserm, U 1127, ICM, Paris, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Hunot
authors.affiliation: Molecular Genetics Section and Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD20892, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY 10032, USA.
authors.forename: C Warren
authors.initials: CW
authors.lastname: Olanow
authors.affiliation: TransThera Consulting Co., Zionsville, IN, 46077, USA.
authors.forename: Kalpana M
authors.initials: KM
authors.lastname: Merchant
authors.affiliation: Institute of Neurodegenerative Diseases, University of Bordeaux, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: Department of Neurology and Feil Family Brain and Mind research Institute, Weill Cornell Medical College, New York NY 10021, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
authors.affiliation: Institute of Neurodegenerative Diseases, University of Bordeaux, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France.
authors.forename: Wassilios G
authors.initials: WG
authors.lastname: Meissner
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein