Residues 2 to 7 of α- synuclein regulate amyloid formation via lipid- dependent and lipid- independent pathways

• 成果类型: Article
• 署名作者: Dewison, Katherine M.; Rowlinson, Benjamin; Machin, Jonathan M.; Crossley, Joel A.; Thacker, Dev; Wilkinson, Martin; Ulamec, Sabine M.; Khan, G. Nasir; Ranson, Neil A.; van Oosten-Hawle, Patricija; Brockwell, David J.; Radford, Sheena E.
• 署名单位: University of Leeds; University of North Carolina; University of North Carolina Charlotte
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14153
• DOI: 10.1073/pnas.2315006121
• 发表日期: 2024-08-20
• 关键词: parkinsons-disease; aggregation; Mutation; amplification; DYNAMICS; families

摘要

Amyloid formation by alpha- synuclein (alpha Syn) occurs in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Deciphering the residues that regulate alpha Syn amyloid fibril formation will not only provide mechanistic insight but may also reveal targets to prevent and treat disease. Previous investigations have identified several regions of alpha Syn to be important in the regulation of amyloid formation, including the non- amyloid-f3 compostudies have also indicated the importance of the N- terminal region of alpha Syn for both its physiological and pathological roles. Here, the role of residues 2 to 7 in the N- terminal in vitro and in vivo. Deletion of these residues (alpha Syn Delta N7) slows the rate of fibril formation in vitro and reduces the capacity of the protein to be recruited by wild- type (alpha SynWT) fibril seeds, despite cryo- EM showing a fibril structure consistent with those of full- length alpha Syn. Strikingly, fibril formation of alpha Syn Delta N7 is not induced by liposomes, despite the protein by expression of alpha SynWT::YFP. Together, the results demonstrate the involvement of residues that may leave the functional role of the protein in membrane binding unperturbed.