Objective: To identify and test the effectiveness of a novel peptide to reduce α-synuclein levels and neurodegeneration in cell and animal models of Parkinson’s disease (PD).
Background: PD is the most common neurodegenerative movement disorder and is characterised by the death of dopaminergic neurons in the substantia nigra (SN). In PD, the protein a-synuclein aggregates into Lewy bodies but also forms oligomers and small fibrils, which are emerging as the pathogenic conformations that drive dopaminergic neurodegeneration in the SN. One potential avenue for therapeutic intervention in PD is to reduce the levels of these toxic forms of a-synuclein.
Method: We used a high-throughput screen to identify a peptide that reduced α-synuclein oligomerization and increased viability in cell systems. The candidate peptide was then tested for efficacy in primary rat cortical neurons, transgenic C. elegans, and rodent models of PD.
Results: Our screen identified a novel protein-protein interaction (PPI) inhibitor peptide that reduced α-synuclein oligomerization in cell systems. We found that this peptide reduced α-synuclein levels in primary rat cortical neurons virally expressing a mutant form of α-synuclein. We also demonstrated a reduction in α-synuclein oligomerization by bimolecular fluorescence complementation in these neurons. In transgenic C. elegans, the PPI inhibitor peptide rescued neurite shortening of dopaminergic neurons due to mutant α-synuclein expression. In rat viral-vector models of PD, we showed a decrease in levels of α-synuclein, including α-synuclein oligomers, in the SN and a reduction of α-synuclein-mediated dopaminergic neurodegeneration. This reduction of dopaminergic neurodegeneration was accompanied by rescue of striatal dopamine levels and behavioural deficits.
Conclusion: The efficacy of this peptide in multiple models of PD supports its further development as a potential new therapeutic for disease modification in PD and other α-synucleinopathies.
To cite this abstract in AMA style:
D. O'Hara, S. Nim, K. Hall, M. Kapadia, M. De Snoo, H. Chau, S. Ngana, C. Corbi-Verge, A. Perez-Riba, S. Kalia, L. Kalia, P. Kim. A novel peptide reduces α-synuclein levels and neurodegeneration in cell, invertebrate, and mammalian models of Parkinson’s disease [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/a-novel-peptide-reduces-%ce%b1-synuclein-levels-and-neurodegeneration-in-cell-invertebrate-and-mammalian-models-of-parkinsons-disease/. Accessed June 15, 2025.« Back to MDS Virtual Congress 2020
MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-peptide-reduces-%ce%b1-synuclein-levels-and-neurodegeneration-in-cell-invertebrate-and-mammalian-models-of-parkinsons-disease/