Enhancing Top-Down Proteomics of Brain Tissue with FAIMS
Open accessPublished version of a preprint
Abstract
Abstract Proteomic investigations of Alzheimer’s and Parkinson’s disease have provided valuable insights into neurodegenerative disorders. Thus far, these investigations have largely been restricted to bottom-up approaches, hindering the degree to which one can characterize a protein’s “intact” state. Top-down proteomics (TDP) overcomes this limitation, however it is typically limited to observing only the most abundant proteoforms and of a relatively small size. Therefore, offline fractionation techniques are commonly used to reduce sample complexity, limiting throughput. A higher throughput alternative is online fractionation, such as gas phase high-field asymmetric waveform ion mobility spectrometry (FAIMS). Utilizing a high complexity sample derived from Alzheimer’s disease brain tissue, we describe how the addition of FAIMS to TDP can robustly improve the depth of proteome coverage. For example, implementation of FAIMS at −50 compensation voltage (CV) more than doubled the mean number of non-redundant proteoforms observed (1,833 ± 17, n = 3), compared to without (754 ± 35 proteoforms). We also found FAIMS can influence the transmission of proteoforms and their charge envelopes based on their size. Importantly, FAIMS enabled the identification of intact amyloid beta (Aβ) proteoforms, including the aggregation-prone Aβ 1-42 variant which is strongly linked to Alzheimer’s disease.
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- Authors
- Fulcher, J. M., Makaju, A., Moore, R. J., Zhou, M., Bennett, D. A., De Jager, P. L., Qian, W.-J., Paša-Tolić, L., & Petyuk, V. A.
- Affiliations
- Pacific Northwest National Laboratory (US)
- Thermo Fisher Scientific (United States) (US)
- Rush University Medical Center (US)
- Department of Neurology, Center for Translational & Computational Neuroimmunology, Columbia University Medical Center, New York, New York 10032, United States
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
- Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99354, United States
- Corresponding author
- Petyuk, Vladislav A.
- ORCID
- Venue
- Journal of Proteome Research
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-04-15
- Volume
- 20
- Issue
- 5
- Pages
- 2780-2795
- ISSN
- 1535-3893 (ISSN-L)
- 1535-3907
- PMC
- PMC8672206
- OpenAlex
- W3153353349
- Cited by
- 68
- References
- 11
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 6 · 2023: 16 · 2022: 12 · 2021: 5
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Journal of Proteome Research (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Institute on Aging (R01 AG015819, U01 AG061356)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- top-down proteomics, FAIMS, gas-phase fractionation, Alzheimer's disease, brain tissue, proteoforms, amyloid-beta, proteome coverage, neurodegenerative diseases
- MeSH terms
- Ion Mobility Spectrometry, Brain, Brain Chemistry, Amyloid beta-Peptides, Proteome, Proteomics
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