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Disturbed brain energy metabolism in a rodent model of DYT-TOR1A dystonia.
Knorr, Susanne; Rauschenberger, Lisa; Muthuraman, Muthuraman; McFleder, Rhonda; Ott, Thomas; Grundmann-Hauser, Kathrin; Higuchi, Takahiro; Volkmann, Jens; Ip, Chi Wang.
Afiliação
  • Knorr S; Department of Neurology, University Hospital Würzburg, 97080, Germany.
  • Rauschenberger L; Department of Neurology, University Hospital Würzburg, 97080, Germany.
  • Muthuraman M; Department of Neurology, University Hospital Würzburg, 97080, Germany.
  • McFleder R; Department of Neurology, University Hospital Würzburg, 97080, Germany.
  • Ott T; Institute for Medical Genetics and Applied Genomics, University of Tübingen, 72076, Germany; Core Facility Transgenic Animals, University Hospital of Tübingen, 72076, Germany; Max Planck Institute for Biological Cybernetics, Tübingen, 72076, Germany.
  • Grundmann-Hauser K; Institute for Medical Genetics and Applied Genomics, University of Tübingen, 72076, Germany; Centre for Rare Diseases, University of Tübingen, 72076, Germany.
  • Higuchi T; Department of Nuclear Medicine, University Hospital Würzburg, 97080, Germany.
  • Volkmann J; Department of Neurology, University Hospital Würzburg, 97080, Germany.
  • Ip CW; Department of Neurology, University Hospital Würzburg, 97080, Germany. Electronic address: ip_c@ukw.de.
Neurobiol Dis ; 194: 106462, 2024 May.
Article em En | MEDLINE | ID: mdl-38442845
ABSTRACT
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 ß-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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenofibrato / Distúrbios Distônicos / Distonia Limite: Animals Idioma: En Revista: Neurobiol Dis Assunto da revista: NEUROLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenofibrato / Distúrbios Distônicos / Distonia Limite: Animals Idioma: En Revista: Neurobiol Dis Assunto da revista: NEUROLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha