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β-synuclein-derived peptides with neuroprotective activity


Year of Publication:
Contact PI Name:
Manfred Windisch
Contact PI Affiliation:
JSW-Research, Forschungslabor Ltd., Graz, Austria
Birgit Hutter-Paier, Edith Schreiner, Robert Wronski
Primary Reference (PubMED ID):
Funding Source:
Not Reported
Study Goal and Principal Findings:

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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Peptide
Therapeutic Agent:
beta Synuclein Peptide Derivatives
Therapeutic Target:
alpha Synuclein
Therapeutic Notes:
alpha-Synuclein has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported
Model Type:
alpha Synuclein
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
Brain-beta Amyloid Peptide 40
Cell Biology
Cell Viability
beta Amyloid Peptides
Drug Concentration-Brain