Dataset Information

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: Dysregulated prenylation has been implicated in the 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 identification of prenylated proteins in various cellular models. Here, transgenic AD mice were treated with C15AlkOPP through intracerebroventricular (ICV) infusion over 13 days. Using prenylomic analysis, 37 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 non-transgenic 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Shelby Auger

LAB HEAD: Mark, D, Distefano

PROVIDER: PXD032350 | Pride | 2022-10-28

REPOSITORIES: Pride

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Publications

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

Jeong Angela A Auger Shelby A SA Maity Sanjay S Fredriksen Kristina K Zhong Rui R Li Ling L Distefano Mark D MD

ACS chemical biology 20220915 10

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 analysi ...[more]

PMID: 36109170

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Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive deterioration of cognitive function. Evidence suggests a role for epigenetic regulation, in particular the cytosine modifications 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC,) in AD. 5hmC is highly enriched in the nervous system and displays neurodevelopment and age-related changes. To determine the role of 5hmC in AD, we performed genome-wide analyses of 5hmC in DNA from prefrontal cortex of post-mortem AD as well as RNA-Seq to correlate changes in methylation status with transcriptional changes. We also utilized the existing AD fly model to further test the functional significance of these epigenetically altered loci. We identified 325 genes containing differentially hydroxymethylated loci (DhMLs) in both the discovery and replication datasets, and these are enriched for pathways involved in neuron projection development and neurogenesis. Of the 325 genes identified, 140 also showed changes in gene expression by RNA-Seq. Proteins encoded by genes identified in the current analysis form direct protein-protein interactions with AD-associated genes, expanding the network of genes implicated in AD. Furthermore, we identified AD-associated single nucleotide polymorphisms (SNPs) located within or near DhMLs, suggesting that these SNPs may identify regions of epigenetic gene regulation that play a role in AD pathogenesis. Finally using the existing AD fly model we showed that some of these genes could modulate the toxicity associated with AD. Our data implicate neuron projection development and neurogenesis pathways as potential targets in AD. These results indicate that incorporating epigenomic and transcriptomic data with GWAS data can expand the known network of genes involved in disease pathogenesis. Combination of epigenome profiling and Drosophila model enables us to identify the epigenetic modifiers of Alzheimer's disease. University of Kentucky Alzheimer's Disease Research Center (3 control, 3 Alzheimer's) and Emory University Alzheimer's Disease Research Center (2 control, 2 Alzheimer's)

Dataset Information

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

Publications

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

Similar Datasets

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