@article{179e04ef883647eaa5aa790fa8143533,
title = "Does Data-Independent Acquisition Data Contain Hidden Gems? A Case Study Related to Alzheimer{\textquoteright}s Disease",
abstract = "One of the potential benefits of using data-independent acquisition (DIA) proteomics protocols is that information not originally targeted by the study may be present and discovered by subsequent analysis. Herein, we reanalyzed DIA data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer{\textquoteright}s disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both autosomal dominant and sporadic AD samples. To explore potential mechanisms that might account for these observations, quantitative analysis of proteins related to isomerization repair and autophagy was performed. Differences consistent with reduced autophagic flux in AD-related samples relative to controls were found for numerous proteins, including most notably p62, a recognized indicator of autophagic inhibition. These results suggest, but do not conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains. This study illustrates that DIA data may contain unforeseen results of interest and may be particularly useful for pilot studies investigating new research directions. In this case, a promising target for future investigations into the therapy and prevention of AD has been identified.",
keywords = "age-related neurodegenerative disease, amyloid, amyloid-beta, aspartic acid, hippocampus, lysosome, neurofibrillary tangle, post-translational modification, proteomics, proteostasis",
author = "Hubbard, {Evan E.} and Heil, {Lilian R.} and Merrihew, {Gennifer E.} and Chhatwal, {Jasmeer P.} and Farlow, {Martin R.} and McLean, {Catriona A.} and Bernardino Ghetti and Newell, {Kathy L.} and Frosch, {Matthew P.} and Bateman, {Randall J.} and Larson, {Eric B.} and Keene, {C. Dirk} and Perrin, {Richard J.} and Montine, {Thomas J.} and MacCoss, {Michael J.} and Julian, {Ryan R.}",
note = "Funding Information: The authors gratefully acknowledge funding from the NIH (R01 AG066626 for RRJ, RF1 AG053959 for M.M. and T.J.M., U01 AG006781 (ACT study) and P30 AG066509 (UW ADRC), and the Nancy and Buster Alvord Endowment (CDK), P30 AG062421 for MPF, U19 AG032438 (DIAN) for RB. Data collection and sharing for this project were supported by The Dominantly Inherited Alzheimer{\textquoteright}s Network (DIAN, UF1AG032438, see List S1 in the Supporting Information) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI). This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society",
year = "2022",
month = jan,
day = "7",
doi = "10.1021/acs.jproteome.1c00558",
language = "English",
volume = "21",
pages = "118--131",
journal = "Journal of Proteome Research",
issn = "1535-3893",
publisher = "American Chemical Society",
number = "1",
}
