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Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

  • Luke A. Esposito
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 18)

Abstract

α-Synuclein is a dynamic protein capable of assuming an ensemble of physiological and pathological structures. Its primary role in Parkinson’s disease (PD) pathogenesis makes it an attractive though nonconventional therapeutic target. An understanding of α-synuclein intra- and intermolecular interactions and posttranslational modifications that lead to its misfolding, aggregation, accumulation, and cell-to-cell prion-like spreading is necessary to inform the design of α-synuclein-directed therapeutics. Native α-synuclein interacts with membranes and plays an important role in synaptic transmission and vesicle trafficking at the presynaptic terminal, though aggregated α-synuclein may be compromised in its ability to perform these functions. In addition to discussing α-synuclein structural biology, this chapter explores the variety of experimental therapeutic approaches currently under investigation that aim to maintain physiological α-synuclein levels, limit toxic aggregates, and lessen effects of misfolded α-synuclein on cellular homeostasis. For example, oligonucleotide-based approaches limit α-synuclein gene expression. In addition, select small molecules and peptides inhibit α-synuclein aggregation at substoichiometric concentrations in favor of less structured, more soluble, and less toxic oligomers that may be better substrates for clearance. Some small molecules also remodel existing α-synuclein fibrils. Modest chemical changes to these small molecules can greatly impact their mechanism of action. Finally, α-synuclein-directed immunotherapy enhances the lysosomal clearance of α-synuclein in experimental models and is currently in clinical trials. Other therapeutic approaches target α-synuclein posttranslational modifications, aim to limit its impact on mitochondria or its ability to alter gene expression in the nucleus.

Keywords

Amyloid Autophagy Disease-modifying Immunotherapy Lewy body Natively unfolded Nutraceutical Off-pathway oligomers Parkinson’s disease Protein misfolding Reactive oxygen species Small molecule α-Synuclein 

Notes

Acknowledgments

I would like to thank Dr. Kelsey Hanson for reading the manuscript and offering helpful suggestions; Dr. Alan Snow, Dr. Sonal Das, Dr. Manfred Weigele, and Marisa-Claire Yadon for helpful discussions; and the Michael J. Fox Foundation for Parkinson’s Disease Research for their support through a LEAPS Award to ProteoTech.

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© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.ProteoTech Inc.KirklandUSA

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