Ion mobility-mass spectrometry and orthogonal gas-phase techniques to study amyloid formation and inhibition

Abstract

Amyloidogenic peptide oligomers are responsible for a variety of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Due to their dynamic, polydisperse, and polymorphic nature, these oligomers are very challenging to characterize using traditional condensed-phase methods. In the last decade, ion mobility-mass spectrometry (IM-MS) and related gas-phase techniques have emerged as a powerful alternative to disentangle the structure and assembly characteristics of amyloid forming systems. This review highlights recent advances in which IM-MS was used to characterize amyloid oligomers and their underlying assembly pathway. In addition, we summarize recent studies in which IM-MS was used to size- and mass-select species for a further spectroscopic investigation and outline the potential of IM-MS as a tool for the screening of amyloid inhibitors.

Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology

“…Due to their heterogeneity and high propensity to aggregate, the low molecular weight Aβ oligomers are not amenable to NMR and X-ray crystallography. As a result, only low resolution structural data from CD, ion mobility mass spectrometry (IM-MS), electron microscopy (EM), transmission electron microscopy (TEM) and atomic force microscopy (AFM) measurements are available [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ]. At the end of the reaction, the fibrils are insoluble and we are left with complicated experiments using isotopic labeling to propose models.…”

Applications of Mass Spectrometry in the Onset of Amyloid Fibril Formation: Focus on the Analysis of Early-Stage Oligomers

“…Various modes of inhibition were identified, including interaction with different species (monomer or oligomer); through different binding patterns (specific, nonspecific, or colloidal), or different effects on aggregation (monomer binding, binding with different conformations of monomer, or disassembly of oligomers). A novel inhibitor (a nonobvious structural mimetic of chloronaphthoquinine-tryptophan) of hIAPP aggregation was discovered accordingly by screening a library of small molecules (Young et al, 2015;Hoffmann et al, 2017). Therefore, IM-MS serves as a promising method in the analysis of amyloid proteins by revealing conformational information of monomers, differentiating oligomeric states of copopulated species, as well as mechanism study of inhibitor binding (Woods et al, 2013).…”

Adding a new separation dimension to MS and LC–MS: What is the utility of ion mobility spectrometry?

“…IM–MS‐based approaches can be used to study amyloid formation, providing information about the assembly pathway and the size and shape of presumably toxic oligomers. IM–MS was first used to separate, analyze, and measure CCSs of individual oligomer species present in equilibrium . A remarkable IM–MS study is reported by Leney et al.…”

“…IM-MS-based approaches can be used to study amyloid formation, providing information about the assembly pathway and the size and shape of presumably toxic oligomers. IM-MS was first used to separate, analyze, and measure CCSs of individual oligomer species present in equilibrium [210]. A remarkable IM-MS study is reported by Leney et al [211] and compares the oligomers formed from wild-type β2m (beta-2-microglobulin) with those formed from a variant of the protein (H51A), during in vitro fibril assembly.…”