Development of a new treatment for Alzheimer's disease and Parkinson's disease using anti-aggregatory beta-synuclein-derived peptides.
The synaptic protein alpha-synuclein is a major constituent of Lewy bodies (LB), pathological neuronal inclusion bodies found in Parkinson's disease (PD), Alzheimer's disease (AD), and other neurodegenerative disorders. Owing to data from patient brains, it was speculated that an imbalance between alpha-synuclein and beta-synuclein might be one of the reasons for formation of LBs and the consequent functional deficits. This was supported by the fact that beta-synuclein is able to prevent abnormal alpha-synuclein aggregation. Transgenic mice overexpressing alpha-synuclein display LB-like inclusions in different brain regions and motor deficits. To verify if re-establishing a normal relation between alpha-synuclein and beta-synuclein is able to prevent the pathology, bigenic mice have been created that overexpress both synucleins. Beta-synuclein decreased formation of LBs by 40% and prevented functional deficits. This is considered as preliminary in vivo proof of antiaggregatory function of beta-synuclein and its potential as therapeutic substance for treatment of neurodegenerative disorders linked with abnormal protein aggregation. Peptide libraries have been synthesized to explore the active structures of beta-synuclein. The first 15 N-terminal amino-acids turned out to be important for the antiaggregatory effect. Further smaller beta-synuclein-derived peptides have screened for antiaggregatory and neuroprotective potency in different tissue-culture systems. Preliminary data suggest some of them can be used as leads for further drug development.
Windisch
Manfred
M
JSW-Research, Institute of Experimental Pharmacology, Graz, Austria. mwindisch@jswresearch.com
Hutter-Paier
Birgit
B
Rockenstein
Edward
E
Hashimoto
Makoto
M
Mallory
Margaret
M
Masliah
Eliezer
E
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D005625:Frontal Lobe / Q000378:metabolism; D016631:Lewy Bodies / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000627:therapeutic use*; D010296:Parietal Lobe / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein
D009419:Nerve Tissue Proteins; C497605:Snca protein, mouse; C497608:Sncb protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein