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: Benjamin Dehay, Mathieu Bourdenx, Philippe Gorry, Serge Przedborski, Miquel Vila, Stephane Hunot, Andrew Singleton, C Warren Olanow, Kalpana M Merchant, Erwan Bezard, Gregory A Petsko, Wassilios G Meissner
• Journal: The Lancet. Neurology (Lancet Neurol) Vol. 14 Issue 8 Pg. 855-866 (Aug 2015) ISSN: 1474-4465 [Electronic] England
• PMID: 26050140 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• alpha-Synuclein

Topics

• Animals
• Drug Discovery
• Humans
• Parkinson Disease (drug therapy, metabolism)
• alpha-Synuclein (chemistry, genetics, metabolism)