Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice
DYT-THAP1 dystonia is a monogenetic form of dystonia, a movement disorder characterized by the involuntary co-contraction of agonistic and antagonistic muscles. The disease is caused by mutations in the THAP1 gene, although the precise mechanisms by which these mutations contribute to the pathophysi...
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| Language: | English |
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003851 |
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| author | Colette Reinhold Susanne Knorr Rhonda L. McFleder Lisa Harder-Rauschenberger Tom Gräfenhan Andreas Schlosser Michael Sendtner Jens Volkmann Chi Wang Ip |
| author_facet | Colette Reinhold Susanne Knorr Rhonda L. McFleder Lisa Harder-Rauschenberger Tom Gräfenhan Andreas Schlosser Michael Sendtner Jens Volkmann Chi Wang Ip |
| author_sort | Colette Reinhold |
| collection | DOAJ |
| description | DYT-THAP1 dystonia is a monogenetic form of dystonia, a movement disorder characterized by the involuntary co-contraction of agonistic and antagonistic muscles. The disease is caused by mutations in the THAP1 gene, although the precise mechanisms by which these mutations contribute to the pathophysiology of dystonia remain unclear. The incomplete penetrance of DYT-THAP1 dystonia, estimated at 40 to 60 %, suggests that an environmental trigger may be required for the manifestation of the disease in genetically predisposed individuals. To investigate the gene-environment interaction in the development of dystonic features, we performed a sciatic nerve crush injury in a genetically predisposed DYT-THAP1 heterozygous knockout mouse model (Thap1+/−). We employed a multi-omic assessment to study the pathophysiological pathways underlying the disease. Phenotypic analysis using an unbiased deep learning algorithm revealed that nerve-injured Thap1+/− mice exhibited significantly more dystonia like movements (DLM) over the course of the 12-week experiment compared to naive Thap1+/− mice. In contrast, nerve-injured wildtype (wt) mice only showed a significant increase in DLM compared to their naive counterpart during the first weeks after injury. Furthermore, at week 11 after nerve crush, nerve-injured Thap1+/− mice displayed significantly more DLM than nerve-injured wt counterparts. Multi-omic analysis of the cerebellum, striatum and cortex in nerve-injured Thap1+/− mice revealed differences that are indicative of an altered energy metabolism compared to naive Thap1+/− and nerve-injured wt animals. These findings suggest that aberrant energy metabolism in brain regions relevant to dystonia may underlie the dystonic phenotype observed in nerve injured Thap1+/− mice. |
| format | Article |
| id | doaj-art-cf58ca6615ee465e9218f6810f310b94 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-cf58ca6615ee465e9218f6810f310b942025-01-24T04:44:39ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106783Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− miceColette Reinhold0Susanne Knorr1Rhonda L. McFleder2Lisa Harder-Rauschenberger3Tom Gräfenhan4Andreas Schlosser5Michael Sendtner6Jens Volkmann7Chi Wang Ip8Department of Neurology, University Hospital of Wuerzburg, GermanyDepartment of Neurology, University Hospital of Wuerzburg, GermanyDepartment of Neurology, University Hospital of Wuerzburg, GermanyDepartment of Neurology, University Hospital of Wuerzburg, GermanyCore Unit Systems Medicine, Medical Faculty, University Wuerzburg, GermanyRudolf Virchow Center for Experimental Biomedicine, University of Wuerzburg, GermanyInstitute of Clinical Neurobiology, University Hospital of Wuerzburg, GermanyDepartment of Neurology, University Hospital of Wuerzburg, GermanyDepartment of Neurology, University Hospital of Wuerzburg, Germany; Corresponding author at: Josef-Schneider-Straße 11, 97080 Wuerzburg, Germany.DYT-THAP1 dystonia is a monogenetic form of dystonia, a movement disorder characterized by the involuntary co-contraction of agonistic and antagonistic muscles. The disease is caused by mutations in the THAP1 gene, although the precise mechanisms by which these mutations contribute to the pathophysiology of dystonia remain unclear. The incomplete penetrance of DYT-THAP1 dystonia, estimated at 40 to 60 %, suggests that an environmental trigger may be required for the manifestation of the disease in genetically predisposed individuals. To investigate the gene-environment interaction in the development of dystonic features, we performed a sciatic nerve crush injury in a genetically predisposed DYT-THAP1 heterozygous knockout mouse model (Thap1+/−). We employed a multi-omic assessment to study the pathophysiological pathways underlying the disease. Phenotypic analysis using an unbiased deep learning algorithm revealed that nerve-injured Thap1+/− mice exhibited significantly more dystonia like movements (DLM) over the course of the 12-week experiment compared to naive Thap1+/− mice. In contrast, nerve-injured wildtype (wt) mice only showed a significant increase in DLM compared to their naive counterpart during the first weeks after injury. Furthermore, at week 11 after nerve crush, nerve-injured Thap1+/− mice displayed significantly more DLM than nerve-injured wt counterparts. Multi-omic analysis of the cerebellum, striatum and cortex in nerve-injured Thap1+/− mice revealed differences that are indicative of an altered energy metabolism compared to naive Thap1+/− and nerve-injured wt animals. These findings suggest that aberrant energy metabolism in brain regions relevant to dystonia may underlie the dystonic phenotype observed in nerve injured Thap1+/− mice.http://www.sciencedirect.com/science/article/pii/S0969996124003851DYT-THAP1Nerve injuryMulti-omicSecond-hit hypothesisDystoniaEnergy metabolism |
| spellingShingle | Colette Reinhold Susanne Knorr Rhonda L. McFleder Lisa Harder-Rauschenberger Tom Gräfenhan Andreas Schlosser Michael Sendtner Jens Volkmann Chi Wang Ip Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice Neurobiology of Disease DYT-THAP1 Nerve injury Multi-omic Second-hit hypothesis Dystonia Energy metabolism |
| title | Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice |
| title_full | Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice |
| title_fullStr | Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice |
| title_full_unstemmed | Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice |
| title_short | Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice |
| title_sort | peripheral nerve injury induces dystonia like movements and dysregulation in the energy metabolism a multi omics descriptive study in thap1 mice |
| topic | DYT-THAP1 Nerve injury Multi-omic Second-hit hypothesis Dystonia Energy metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003851 |
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