CNS & Neurological Disorders - Drug Targets

(Formerly Current Drug Targets - CNS & Neurological Disorders)

Stephen D. Skaper  
Department of Pharmaceutical and Pharmacological Sciences
University of Padova


Drug Targets from Genetics: Alpha-Synuclein

Author(s): Karin M. Danzer and Pamela J. McLean

Affiliation: Department of Neurology,Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street, Charlestown, MA 02129, USA.


One of the critical issues in Parkinson disease (PD) research is the identity of the specific toxic, pathogenic moiety. In PD, mutations in alpha-synuclein (αsyn) or multiplication of the SNCA gene encoding αsyn, result in a phenotype of cellular inclusions, cell death, and brain dysfunction. While the historical point of view has been that the macroscopic aggregates containing αsyn are the toxic species, in the last several years evidence has emerged that suggests instead that smaller soluble species - likely oligomers containing misfolded αsyn - are actually the toxic moiety and that the fibrillar inclusions may even be a cellular detoxification pathway and less harmful. If soluble misfolded species of αsyn are the toxic moieties, then cellular mechanisms that degrade misfolded αsyn would be neuroprotective and a rational target for drug development. In this review we will discuss the fundamental mechanisms underlying αsyn toxicity including oligomer formation, oxidative stress, and degradation pathways and consider rational therapeutic strategies that may have the potential to prevent or halt αsyn induced pathogenesis in PD.

Keywords: Alpha-synuclein, Parkinson's Disease, Chaperones, Oligomers, Heat shock proteins, oxidative stress, Degradation, Neurodegeneration, AMPA, MPTP, PINK1, Geldanamycin, Gene therapy, CHIP, Chaperone-mediated autophagy

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Article Details

Page: [712 - 723]
Pages: 12
DOI: 10.2174/187152711797247867