Beta-Synuclein-derived peptides with neuroprotective activity: an alternative treatment of neurodegenerative disorders?
The 140-amino-acid protein alpha-synuclein (alpha-syn) is the major constituent of Lewy bodies. The protein interacts with several intracellular signal transduction pathways. Reasons for onset of abnormal aggregation of alpha-syn are unclear. Metal ions, oxidative stress, and beta-amyloid 1-42 (Abeta1-42) are important induction factors for alpha-syn aggregation. beta-Synuclein (beta-syn) can counteract alpha-syn aggregation. Cross-breeding of beta-syn transgenic mice with animals overexpressing alpha-syn significantly decreased alpha-syn-positive neuronal inclusion bodies and improved motor function. This was an important proof of concept for the role of beta-syn in regulating alpha-syn aggregation. A drug discovery program based on peptide derivatives (N-terminal amino acids 1-15) of beta-syn was initiated. For screening, tissue culture models simulating disease-specific conditions were utilized. They protected against growth factor withdrawal, Abeta toxicity, and oxidative stress. Three peptides were selected (KEGV, SMAKEGV, MDFMKGLSMAKE) for in vivo studies because they also decreased expression of Abeta1-40 and Abeta1-42. First, in vivo experiments were made in human amyloid precursor protein (APP [Swedish and London mutation]) transgenic mice, as well as alpha-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.
Windisch
Manfred
M
JSW-Research, Forschungslabor Ltd., A-8020 Graz, Austria. mwindisch@jswresearch.com
Hutter-Paier
Birgit
B
Schreiner
Edith
E
Wronski
Robert
R
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016631:Lewy Bodies / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C497604:SNCA protein, human; C497607:SNCB protein, human; C497605:Snca protein, mouse; C497608:Sncb protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D051846:beta-Synuclein