Amyloid fibrils prepared using an acetylated and methyl amidated peptide model of the ?-Synuclein NAC 71-82 amino acid stretch contain an additional cross-? structure also found in prion proteins.

ABSTRACT: The 71-82 fragment of the non-amyloid-? component (NAC) region of the Parkinson's disease (PD) and dementia with Lewy bodies (DLB) related protein ?-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 ?-Synuclein are amyloid and contain, in addition to the cross-? structure detected in the full-length protein fibrils, a cross-? 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 ?-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 ?-sheet motif. Due to its expected toxicity, this ?-sheet motif may be a promising molecular target for the development of therapeutic strategies for PD and DLB.

SUBMITTER: Nasstrom T 

PROVIDER: S-EPMC6828723 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature