TY  - JOUR
AU  - Kilzheimer, Alexander
AU  - Hentrich, Thomas
AU  - Rotermund, Carola
AU  - Kahle, Philipp J
AU  - Schulze-Hentrich, Julia M
TI  - Failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice.
JO  - Human molecular genetics
VL  - 32
IS  - 3
SN  - 0964-6906
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2022-01442
SP  - 450 - 461
PY  - 2023
N1  - CC BY: https://creativecommons.org/licenses/by/4.0/
AB  -  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.
KW  - Mice
KW  - Animals
KW  - Mice, Transgenic
KW  - alpha-Synuclein: genetics
KW  - alpha-Synuclein: metabolism
KW  - Parkinson Disease: genetics
KW  - Parkinson Disease: metabolism
KW  - Diet, High-Fat: adverse effects
KW  - Gene Expression Profiling
KW  - Mice, Inbred C57BL
KW  - alpha-Synuclein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9851747
C6  - pmid:36001352
DO  - DOI:10.1093/hmg/ddac205
UR  - https://pub.dzne.de/record/165137
ER  -