Details

Autor(en) / Beteiligte

• Ulamec, Sabine M.
• Maya-Martinez, Roberto
• Byrd, Emily J.
• Dewison, Katherine M.
• Xu, Yong
• Willis, Leon F.
• Sobott, Frank
• Heath, George R.
• van Oosten Hawle, Patricija
• Buchman, Vladimir L.
• Radford, Sheena E.
• Brockwell, David J.

Titel

Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein

Ist Teil von

• Nature communications, 2022-08, Vol.13 (1), p.4986-4986, Article 4986

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2022

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Alpha-synuclein (αSyn) is a protein involved in neurodegenerative disorders including Parkinson’s disease. Amyloid formation of αSyn can be modulated by the ‘P1 region’ (residues 36-42). Here, mutational studies of P1 reveal that Y39A and S42A extend the lag-phase of αSyn amyloid formation in vitro and rescue amyloid-associated cytotoxicity in C. elegans . Additionally, L38I αSyn forms amyloid fibrils more rapidly than WT, L38A has no effect, but L38M does not form amyloid fibrils in vitro and protects from proteotoxicity. Swapping the sequence of the two residues that differ in the P1 region of the paralogue γSyn to those of αSyn did not enhance fibril formation for γSyn. Peptide binding experiments using NMR showed that P1 synergises with residues in the NAC and C-terminal regions to initiate aggregation. The remarkable specificity of the interactions that control αSyn amyloid formation, identifies this region as a potential target for therapeutics, despite their weak and transient nature. The authors of this work characterize the effect of amino acid substitution on α-synuclein (α-Syn) aggregation. Residues 38 and 42 (in addition to 39) within the P1 region of α-Syn affect amyloid formation. The effect of substitution at position 38 is dependent on the amino-acid introduced, suggesting that specific interactions control α -Syn aggregation.