The buildup of amyloid fibrils in the brain is known to cause many neurodegenerative diseases. These amyloid fibrils form when proteins misfold into a conformation rich in β-sheet. These β-sheets can aggregate with one another to form the amyloid fibrils responsible for the break-down of specific neurological processes. α-synuclein is a pre-synaptic protein classified as a SNARE-protein chaperone enabling neurotransmitter release. α-synuclein is natively disordered, but is known to misfold into a β-sheet conformation. Mutations and overexpression of α-synuclein cause the protein to aggregate; these aggregates are found in the form of Lewy bodies in the brains of Parkinson’s disease patients. Parkinson’s disease progresses gradually and impedes motor function.<br/><br/>Previous research has shown that the deletion of residues 85-94 of the α-synuclein protein (Δ85-94 AGSIAAATGF) inhibits amyloid formation. In an attempt to identify the nucleating region of protein misfolding, we synthesized all tripeptides and tetrapeptides of this sequence and analyzed their structural tendencies using infrared spectroscopy.<br/><br/>Peptide synthesis was conducted using standard Fmoc-chemistry on a solid phase Rink AM amide resin support to ensure the C-terminus was amidated. Prior to cleavage from the resin, the peptide was acetylated at the N-terminus. These two capping groups eliminate charge effects and allow the peptides to mimic their presence in the full length protein. Our infrared analysis of each peptide showed peaks indicative of β-sheet formation in GSIA only; all other peptides appear to adopt a random coil conformation. Mixing experiments that combined GSIA with the disordered peptides, were conducted to determine whether GSIA could induce b-sheet formation in disordered peptides. Our results indicate that while this is possible in some cases, other disordered samples instead inhibit b-sheet formation in GSIA.

α-Synuclein misfolding and β-sheet aggregation in Parkinson’s disease

251st National Meeting (2016)

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