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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Go to the profile of Jody Mason

Jody Mason

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

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