Disturbed brain energy metabolism in a rodent model of DYT-TOR1A dystonia

  • DYT-TOR1A (DYT1) dystonia, characterized by reduced penetrance and suspected environmental triggers, is explored using a “second hit” DYT-TOR1A rat model. We aim to investigate the biological mechanisms driving the conversion into a dystonic phenotype, focusing on the striatum's role in dystonia pathophysiology. Sciatic nerve crush injury was induced in ∆ETorA rats, lacking spontaneous motor abnormalities, and wild-type (wt) rats. Twelve weeks post-injury, unbiased RNA-sequencing was performed on the striatum to identify differentially expressed genes (DEGs) and pathways. Fenofibrate, a PPARα agonist, was introduced to assess its effects on gene expression. 18F-FDG autoradiography explored metabolic alterations in brain networks. Low transcriptomic variability existed between naïve wt and ∆ETorA rats (17 DEGs). Sciatic nerve injury significantly impacted ∆ETorA rats (1009 DEGs) compared to wt rats (216 DEGs). Pathway analyses revealed disruptions in energy metabolism,DYT-TOR1A (DYT1) dystonia, characterized by reduced penetrance and suspected environmental triggers, is explored using a “second hit” DYT-TOR1A rat model. We aim to investigate the biological mechanisms driving the conversion into a dystonic phenotype, focusing on the striatum's role in dystonia pathophysiology. Sciatic nerve crush injury was induced in ∆ETorA rats, lacking spontaneous motor abnormalities, and wild-type (wt) rats. Twelve weeks post-injury, unbiased RNA-sequencing was performed on the striatum to identify differentially expressed genes (DEGs) and pathways. Fenofibrate, a PPARα agonist, was introduced to assess its effects on gene expression. 18F-FDG autoradiography explored metabolic alterations in brain networks. Low transcriptomic variability existed between naïve wt and ∆ETorA rats (17 DEGs). Sciatic nerve injury significantly impacted ∆ETorA rats (1009 DEGs) compared to wt rats (216 DEGs). Pathway analyses revealed disruptions in energy metabolism, specifically in fatty acid β-oxidation and glucose metabolism. Fenofibrate induced gene expression changes in wt rats but failed in ∆ETorA rats. Fenofibrate increased dystonia-like movements in wt rats but reduced them in ∆ETorA rats. 18F-FDG autoradiography indicated modified glucose metabolism in motor and somatosensory cortices and striatum in both ∆ETorA and wt rats post-injury. Our findings highlight perturbed energy metabolism pathways in DYT-TOR1A dystonia, emphasizing compromised PPARα agonist efficacy in the striatum. Furthermore, we identify impaired glucose metabolism in the brain network, suggesting a potential shift in energy substrate utilization in dystonic DYT-TOR1A rats. These results contribute to understanding the pathophysiology and potential therapeutic targets for DYT-TOR1A dystonia.show moreshow less

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Metadaten
Author:Susanne Knorr, Lisa Rauschenberger, Muthuraman MuthuramanORCiDGND, Rhonda McFleder, Thomas Ott, Kathrin Grundmann-Hauser, Takahiro Higuchi, Jens Volkmann, Chi Wang Ip
URN:urn:nbn:de:bvb:384-opus4-1139379
Frontdoor URLhttps://opus.bibliothek.uni-augsburg.de/opus4/113937
ISSN:0969-9961OPAC
Parent Title (English):Neurobiology of Disease
Publisher:Elsevier BV
Type:Article
Language:English
Year of first Publication:2024
Publishing Institution:Universität Augsburg
Release Date:2024/07/10
Volume:194
First Page:106462
DOI:https://doi.org/10.1016/j.nbd.2024.106462
Institutes:Fakultät für Angewandte Informatik
Fakultät für Angewandte Informatik / Institut für Informatik
Fakultät für Angewandte Informatik / Institut für Informatik / Professur für Informatik in der Medizintechnik
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):CC-BY-NC 4.0: Creative Commons: Namensnennung - Nicht kommerziell (mit Print on Demand)