Tilted properties of the 67-78 fragment of alpha-synuclein are responsible for membrane destabilization and neurotoxicity.
Alpha-synuclein is a 140 residue protein associated with Parkinson's disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of alpha-synuclein aggregated into amyloid fibrils. Other amyloidogenic proteins, such as the beta amyloid peptide involved in Alzheimer's disease and the prion protein (PrP) associated with Creuztfeldt-Jakob's disease, are known to possess "tilted peptides". These peptides are short protein fragments that adopt an oblique orientation at a hydrophobic/hydrophilic interface, which enables destabilization of the membranes. In this paper, sequence analysis and molecular modelling predict that the 67-78 fragment of alpha-synuclein is a tilted peptide. Its destabilizing properties were tested experimentally. The alpha-synuclein 67-78 peptide is able to induce lipid mixing and leakage of unilamellar liposomes. The neuronal toxicity, studied using human neuroblastoma cells, demonstrated that the alpha-synuclein 67-78 peptide induces neurotoxicity. A mutant designed by molecular modelling to be amphipathic was shown to be significantly less fusogenic and toxic than the wild type. In conclusion, we have identified a tilted peptide in alpha-synuclein, which could be involved in the toxicity induced during amyloidogenesis of alpha-synuclein.
Crowet
Jean-Marc
JM
Gembloux Agricultural University, Centre de Biophysique Moléculaire Numérique, 2 Passage des Déportés, B-5030 Gembloux, Belgium. crowet.jm@fsagx.ac.be
Lins
Laurence
L
Dupiereux
Ingrid
I
Elmoualija
Benaïssa
B
Lorin
Aurélien
A
Charloteaux
Benoit
B
Stroobant
Vincent
V
Heinen
Ernst
E
Brasseur
Robert
R
D002942:Circular Dichroism; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology; D008958:Models, Molecular; D009498:Neurotoxins / Q000633:toxicity; D010300:Parkinson Disease / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*; D010743:Phospholipids; D011487:Protein Conformation; D013314:Stress, Mechanical; D051844:alpha-Synuclein / Q000032:analysis / Q000737:chemistry*
D009498:Neurotoxins; D010446:Peptide Fragments; D010743:Phospholipids; D051844:alpha-Synuclein