Towards peptide-based inhibitors as therapies for Parkinson's disease

Peptides for Parkinson's?

Go to the profile of Jody Mason
Dec 10, 2015
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The evidence for α-synuclein (α-syn) as a key player in Parkinson’s disease (PD) pathology is compelling despite the fact that the native function of the protein has yet to be fully elucidated [1]. For example, synthetic α-syn aggregates that are characteristic of synucleinopathies lead to β-sheet rich amyloid structures similar to those found in Lewy bodies [2]. These structures lead to cell death with the majority of point mutations associated with early onset PD (A30P, E46K, H50Q, G51D, A53T) clustered within a small region of the SNCA gene, which influence the rate and extent of aggregation which correlates with toxicity [3–6]. Until recently it was thought that the native state of α-syn was structurally disordered [7] before undergoing a structural conversion to β-sheet and amyloid. However, recent albeit controversial findings suggest that the native state is a monomer that self-associates on lipids to form a helical tetramer, which exists in the crowded molecular environment of the cell but does not accumulate in vitro [8]. Several α-syn point mutations have been hypothesized to destabilize this proposed tetramer, leading to increased levels of monomer that then aggregate [9]. In our own experiments, the libraries have been based on the 46–54 region of α-syn where the majority of mutations associated with early onset PD are found. In these experiments, the identified inhibitors have been found to prevent α-syn amyloid formation and lead to significant reductions in toxicity [10].

There are some exciting advances in the development of peptides and mimetics to bind to and prevent toxicity associated with α-syn amyloid formation. Coupled with recent developments in structural information relating to amyloid-based systems [11], and the increasing ability to readily modify peptides to deal with limitations in their druggability, there is now considerable optimism for peptide-based drug discovery for a-syn.

Read more in Mason J.M. & Fairlie D.P. Towards peptide-based inhibitors as therapies for Parkinson's disease Future Med. Chem. 7, 2103-5 (2015).

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9. Dettmer U, Newman AJ, Soldner F et al. Parkinson-causing alpha-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat. Commun. 6, 7314 (2015).
10. Cheruvara H, Allen-Baume VL, Kad NM, Mason JM. Intracellular screening of a peptide library to derive a potent peptide inhibitor of alpha-synuclein aggregation. J. Biol. Chem. 290(12), 7426–7435 (2015).
11. Meier BH, Bockmann A. The structure of fibrils from ‘misfolded’ proteins. Curr. Opin. Struct. Biol. 30, 43–49 (2015).

Go to the profile of Jody Mason

Jody Mason

Senior Lecturer in Biochemistry at University of Bath, University of Bath

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