Abstract
The 71-82 fragment of the non-amyloid-β component (NAC) region of the Parkinson's disease (PD) and dementia with Lewy bodies (DLB) related protein α-Synuclein, has been reported to be important during protein misfolding. Although reports have demonstrated the importance of this fragment for the aggregation properties of the full-length protein, its exact role in pre-fibrillar oligomerisation, fibrillar growth and morphology has not yet been fully elucidated. Here, we provide evidence that fibrils prepared from an acetylated and methyl amidated peptide of the NAC 71-82 amino acid stretch of α-Synuclein are amyloid and contain, in addition to the cross-β structure detected in the full-length protein fibrils, a cross-β structure previously observed in prion proteins. These results shed light on the aggregation propensity of the NAC 71-82 amino acid stretch of the full-length protein but also the roles of the N- and C-terminal domains of α-Synuclein in balancing this aggregation propensity. The results also suggest that early aggregated forms of the capped NAC 71-82 peptide generated structures were stabilised by an anti-parallel and twisted β-sheet motif. Due to its expected toxicity, this β-sheet motif may be a promising molecular target for the development of therapeutic strategies for PD and DLB.