Failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice

Nutritional influences have been discussed as potential modulators of Parkinson’s disease (PD) pathology through various epidemiological and physiological studies. In animal models, a high-fat diet (HFD) with greater intake of lipid-derived calories leads to accelerated disease onset and progression...

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Autores principales: Kilzheimer, Alexander, Hentrich, Thomas, Rotermund, Carola, Kahle, Philipp J, Schulze-Hentrich, Julia M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9851747/
https://www.ncbi.nlm.nih.gov/pubmed/36001352
http://dx.doi.org/10.1093/hmg/ddac205
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author Kilzheimer, Alexander
Hentrich, Thomas
Rotermund, Carola
Kahle, Philipp J
Schulze-Hentrich, Julia M
author_facet Kilzheimer, Alexander
Hentrich, Thomas
Rotermund, Carola
Kahle, Philipp J
Schulze-Hentrich, Julia M
author_sort Kilzheimer, Alexander
collection PubMed
description Nutritional influences have been discussed as potential modulators of Parkinson’s disease (PD) pathology through various epidemiological and physiological studies. In animal models, a high-fat diet (HFD) with greater intake of lipid-derived calories leads to accelerated disease onset and progression. The underlying molecular mechanisms of HFD-induced aggravated pathology, however, remain largely unclear. In this study, we aimed to further illuminate the effects of a fat-enriched diet in PD by examining the brainstem and hippocampal transcriptome of alpha-synuclein transgenic mice exposed to a life-long HFD. Investigating individual transcript isoforms, differential gene expression and co-expression clusters, we observed that transcriptional differences between wild-type (WT) and transgenic animals intensified in both regions under HFD. Both brainstem and hippocampus displayed strikingly similar transcriptomic perturbation patterns. Interestingly, expression differences resulted mainly from responses in WT animals to HFD, while these genes remained largely unchanged or were even slightly oppositely regulated by diet in transgenic animals. Genes and co-expressed gene groups exhibiting this dysregulation were linked to metabolic and mitochondrial pathways. Our findings propose the failure of metabolic adaptions as the potential explanation for accelerated disease unfolding under exposure to HFD. From the identified clusters of co-expressed genes, several candidates lend themselves to further functional investigations.
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spelling pubmed-98517472023-01-20 Failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice Kilzheimer, Alexander Hentrich, Thomas Rotermund, Carola Kahle, Philipp J Schulze-Hentrich, Julia M Hum Mol Genet Original Article Nutritional influences have been discussed as potential modulators of Parkinson’s disease (PD) pathology through various epidemiological and physiological studies. In animal models, a high-fat diet (HFD) with greater intake of lipid-derived calories leads to accelerated disease onset and progression. The underlying molecular mechanisms of HFD-induced aggravated pathology, however, remain largely unclear. In this study, we aimed to further illuminate the effects of a fat-enriched diet in PD by examining the brainstem and hippocampal transcriptome of alpha-synuclein transgenic mice exposed to a life-long HFD. Investigating individual transcript isoforms, differential gene expression and co-expression clusters, we observed that transcriptional differences between wild-type (WT) and transgenic animals intensified in both regions under HFD. Both brainstem and hippocampus displayed strikingly similar transcriptomic perturbation patterns. Interestingly, expression differences resulted mainly from responses in WT animals to HFD, while these genes remained largely unchanged or were even slightly oppositely regulated by diet in transgenic animals. Genes and co-expressed gene groups exhibiting this dysregulation were linked to metabolic and mitochondrial pathways. Our findings propose the failure of metabolic adaptions as the potential explanation for accelerated disease unfolding under exposure to HFD. From the identified clusters of co-expressed genes, several candidates lend themselves to further functional investigations. Oxford University Press 2022-08-24 /pmc/articles/PMC9851747/ /pubmed/36001352 http://dx.doi.org/10.1093/hmg/ddac205 Text en © The Author(s) 2022. Published by Oxford University Press. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Kilzheimer, Alexander
Hentrich, Thomas
Rotermund, Carola
Kahle, Philipp J
Schulze-Hentrich, Julia M
Failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice
title Failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice
title_full Failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice
title_fullStr Failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice
title_full_unstemmed Failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice
title_short Failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice
title_sort failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9851747/
https://www.ncbi.nlm.nih.gov/pubmed/36001352
http://dx.doi.org/10.1093/hmg/ddac205
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