The N-terminal repeat domain of alpha-synuclein inhibits beta-sheet and amyloid fibril formation.

The conversion of alpha-synuclein into amyloid fibrils in the substantia nigra is linked to Parkinson's disease. Alpha-synuclein is natively unfolded in solution, but can be induced to form either alpha-helical or beta-sheet structure depending on its concentration and the solution conditions. The N-terminus of alpha-synuclein comprises seven 11-amino acid repeats (XKTKEGVXXXX) which can form an amphipathic alpha-helix. Why seven repeats, rather than six or eight, survived the evolutionary process is not clear. To probe this question, two sequence variants of alpha-synuclein, one with two fewer (del2) and one with two additional (plus2) repeats, were studied. As compared to wild-type alpha-synuclein, the plus2 variant disfavors the formation of beta-sheet-rich oligomers, including amyloid fibrils. In contrast, the truncated variant, del2, favors beta-sheet and fibril formation. We propose that the repeat number in WT alpha-synuclein represents an evolutionary balance between the functional conformer of alpha-synuclein (alpha-helix and/or random coil) and its pathogenic beta-sheet conformation. N-terminal truncation of alpha-synuclein may promote pathogenesis.