Researchers Use Novel Techniques to Uncover Structural Properties of α-Synuclein Dimer

In a new study, researchers at the University of Edinburgh have utilized a novel approach to determine the location of the α-Synuclein dimer interface using native top-down fragmentation and isotope depletion-mass spectrometry (1).

Their study, published in the Journal of the American Society for Mass Spectrometry, provides insights into the structural properties of a naturally occurring dimeric species of α-Synuclein, the primary proteinaceous component of pathology-associated Lewy body inclusions in Parkinson’s disease (PD) (1).

Senior man suffering from Parkinson syndrome on grey background | Image Credit: © Pixel-Shot - stock.adobe.com

Ion mobility-mass spectrometry (IM–MS) and native top-down electron capture dissociation fragmentation was used to elucidate the structural properties of the stable dimeric species of αSyn. The researchers also integrated a novel method for generating isotopically depleted proteins into their workflow to increase the signal-to-noise (S/N) ratio and reduce the spectral complexity of fragmentation data. By using this new method, the research team enabled the accurate and confident assignment of fragments unique to the αSyn dimer and the inference of structural information about this species.

Their approach revealed that the αSyn dimer demonstrates a C-terminal to C-terminal interaction between the monomer subunits because they identified fragments unique to the dimer. This sheds light on the endogenous multimeric species of αSyn, which is associated with Parkinson’s disease, but it is yet to be fully understood.

αSyn is a 140-residue intrinsically disordered protein, and its association with PD makes it a crucial protein for study. However, the protein's endogenous structure and physiological roles are yet to be fully understood. This study provides a promising approach for further investigation into the structural properties of endogenous multimeric species of αSyn.

This work is also an essential step towards identifying structural features and binding partners that influence αSyn function in vivo, and it provides an essential foundation for designing therapeutic strategies that target the multimeric species of αSyn.

In summary, this study contributes to the growing body of research on αSyn and its association with Parkinson’s disease. The approach used in this study provides a promising platform for further investigation into the structural properties of αSyn and other intrinsically disordered proteins.

Reference

(1) Jeacock, K.; Chappard, A.; Gallagher, K. J.; Mackay, C. L.; Kilgour, D. P. A.; Horrocks, M. H.; Kunath, T.; Clarke, D. J. Determining the Location of the α-Synuclein Dimer Interface Using Native Top-Down Fragmentation and Isotope Depletion-Mass Spectrometry. J. Am. Soc. Mass Spectrom. 2023, ASAP. DOI: 10.1021/jasms.2c00339