, Volume 24, Issue 1, pp 155-165

β-synuclein-derived peptides with neuroprotective activity

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Abstract

The 140-amino-acid protein α-synuclein (α-syn) is the major constituent of Lewy bodies. The protein interacts with several intracellular signal transduction pathways. Reasons for onset of abnormal aggregation of α-syn are unclear. Metal ions, oxidative stress, and β-amyloid 1–42 (Aβ1–42) are important induction factors for α-syn aggregation. β-Synuclein (β-syn) can counteract α-syn aggregation. Cross-breeding of β-syn transgenic mice with animals overexpressing α-syn significantly decreased α-syn-positive neuronal inclusion bodies and improved motor function. This was an important proof of concept for the role of β-syn in regulating α-syn aggregation. A drug discovery program based on peptide derivatives (N-terminal amino acids 1–15) of β-syn was initiated. For screening, tissue culture models simulating disease-specific conditions were utilized. They protected against growth factor withdrawal, Aβ toxicity, and oxidative stress. Three peptides were selected (KEGV, SMAKEGV, MDFMKGLSMAKE) for in vivo studies because they also decreased expression of Aβ1–40 and Aβ1–42. First, in vivo experiments were made in human amyloid precursor protein (APP [Swedish and London mutation]) transgenic mice, as well as α-syn transgenic mice. Treatment was performed with the peptides as an intraperitoneal injection or as intranasal droplets for 2 mo. Behavioral studies in APP transgenic mice were performed after 1 and 2 mo of treatment and showed clear effects of these peptides.