In Vivo Prenylomic Profiling in the Brain of a Transgenic Mouse Model of Alzheimer's Disease Reveals Increased Prenylation of a Key Set of Proteins

Angela Jeong; Shelby A. Auger; Sanjay Maity; Kristina Fredriksen; Rui Zhong; Ling Li; Mark D. Distefano

doi:10.1021/acschembio.2c00486

In Vivo Prenylomic Profiling in the Brain of a Transgenic Mouse Model of Alzheimer's Disease Reveals Increased Prenylation of a Key Set of Proteins

Angela Jeong, Shelby A. Auger, Sanjay Maity, Kristina Fredriksen, Rui Zhong, Ling Li, Mark D. Distefano

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Dysregulation of protein prenylation has been implicated in many diseases, including Alzheimer's disease (AD). Prenylomic analysis, the combination of metabolic incorporation of an isoprenoid analogue (C15AlkOPP) into prenylated proteins with a bottom-up proteomic analysis, has allowed the identification of prenylated proteins in various cellular models. Here, transgenic AD mice were administered with C15AlkOPP through intracerebroventricular (ICV) infusion over 13 days. Using prenylomic analysis, 36 prenylated proteins were enriched in the brains of AD mice. Importantly, the prenylated forms of 15 proteins were consistently upregulated in AD mice compared to nontransgenic wild-type controls. These results highlight the power of this in vivo metabolic labeling approach to identify multiple post-translationally modified proteins that may serve as potential therapeutic targets for a disease that has proved refractory to treatment thus far. Moreover, this method should be applicable to many other types of protein modifications, significantly broadening its scope.

Original language	English (US)
Pages (from-to)	2863-2876
Number of pages	14
Journal	ACS Chemical Biology
Volume	17
Issue number	10
DOIs	https://doi.org/10.1021/acschembio.2c00486
State	Published - Oct 21 2022

Bibliographical note

Funding Information:
This work was supported in part by the National Institute of Health grants RF1AG056976 (L.L. and M.D.D.), R35GM141853 (M.D.D.), R21AG056025 (L.L.), and RF1AG058081 (L.L.). S.A.A. was supported by National Institute of Health Training Grants T32 GM132029 and T32 AG029796.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

Keywords

Animals
Mice
Alzheimer Disease/drug therapy
Mice, Transgenic
Proteomics/methods
Protein Prenylation
Proteins/metabolism
Disease Models, Animal
Brain/metabolism
Terpenes/metabolism

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural

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10.1021/acschembio.2c00486

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abstract = "Dysregulation of protein prenylation has been implicated in many diseases, including Alzheimer's disease (AD). Prenylomic analysis, the combination of metabolic incorporation of an isoprenoid analogue (C15AlkOPP) into prenylated proteins with a bottom-up proteomic analysis, has allowed the identification of prenylated proteins in various cellular models. Here, transgenic AD mice were administered with C15AlkOPP through intracerebroventricular (ICV) infusion over 13 days. Using prenylomic analysis, 36 prenylated proteins were enriched in the brains of AD mice. Importantly, the prenylated forms of 15 proteins were consistently upregulated in AD mice compared to nontransgenic wild-type controls. These results highlight the power of this in vivo metabolic labeling approach to identify multiple post-translationally modified proteins that may serve as potential therapeutic targets for a disease that has proved refractory to treatment thus far. Moreover, this method should be applicable to many other types of protein modifications, significantly broadening its scope.",

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author = "Angela Jeong and Auger, {Shelby A.} and Sanjay Maity and Kristina Fredriksen and Rui Zhong and Ling Li and Distefano, {Mark D.}",

note = "Funding Information: This work was supported in part by the National Institute of Health grants RF1AG056976 (L.L. and M.D.D.), R35GM141853 (M.D.D.), R21AG056025 (L.L.), and RF1AG058081 (L.L.). S.A.A. was supported by National Institute of Health Training Grants T32 GM132029 and T32 AG029796. Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",

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AU - Fredriksen, Kristina

AU - Zhong, Rui

AU - Li, Ling

AU - Distefano, Mark D.

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PY - 2022/10/21

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N2 - Dysregulation of protein prenylation has been implicated in many diseases, including Alzheimer's disease (AD). Prenylomic analysis, the combination of metabolic incorporation of an isoprenoid analogue (C15AlkOPP) into prenylated proteins with a bottom-up proteomic analysis, has allowed the identification of prenylated proteins in various cellular models. Here, transgenic AD mice were administered with C15AlkOPP through intracerebroventricular (ICV) infusion over 13 days. Using prenylomic analysis, 36 prenylated proteins were enriched in the brains of AD mice. Importantly, the prenylated forms of 15 proteins were consistently upregulated in AD mice compared to nontransgenic wild-type controls. These results highlight the power of this in vivo metabolic labeling approach to identify multiple post-translationally modified proteins that may serve as potential therapeutic targets for a disease that has proved refractory to treatment thus far. Moreover, this method should be applicable to many other types of protein modifications, significantly broadening its scope.

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In Vivo Prenylomic Profiling in the Brain of a Transgenic Mouse Model of Alzheimer's Disease Reveals Increased Prenylation of a Key Set of Proteins

Abstract

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Keywords

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