%0 Journal Article %1 Reinhold_2024 %A Reinhold, Colette %A Knorr, Susanne %A McFleder, Rhonda L. %A Rauschenberger, Lisa %A Muthuraman, Muthuraman %A Arampatzi, Panagiota %A Gräfenhan, Tom %A Schlosser, Andreas %A Sendtner, Michael %A Volkmann, Jens %A Ip, Chi Wang %D 2024 %I Elsevier BV %J Neurobiology of Disease %K myown %P 106453 %R 10.1016/j.nbd.2024.106453 %T Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model %U http://dx.doi.org/10.1016/j.nbd.2024.106453 %X DYT-TOR1A dystonia is the most common monogenic dystonia characterized by involuntary muscle contractions and lack of therapeutic options. Despite some insights into its etiology, the disease’s pathophysiology remains unclear. The reduced penetrance of about 30% suggests that extragenetic factors are needed to develop a dystonic phenotype. In order to systematically investigate this hypothesis, we induced a sciatic nerve crush injury in a genetically predisposed DYT-TOR1A mouse model (DYT1KI) to evoke a dystonic phenotype. Subsequently, we employed a multi-omic approach to uncover novel pathophysiological pathways that might be responsible for this condition. Using an unbiased deep-learning-based characterization of the dystonic phenotype showed that nerve-injured DYT1KI animals exhibited significantly more dystonia-like movements (DLM) compared to naive DYT1KI animals. This finding was noticeable as early as two weeks following the surgical procedure. Furthermore, nerve injured DYT1KI mice displayed significantly more DLM than nerve-injured wildtype (wt) animals starting at 6 weeks post injury. In the cerebellum of nerve-injured wt mice, multi-omic analysis pointed towards regulation in translation related processes. These observations were not made in the cerebellum of nerve-injured DYT1KI mice; instead, they were localized to the cortex and striatum. Our findings indicate a lack of effective translational rescue mechanisms in the cerebellum of phenotypic DYT1KI mice that exhibit DLM, while translation dysregulations in the cortex and striatum likely contribute to the dystonic phenotype.

@article{Reinhold_2024, abstract = {DYT-TOR1A dystonia is the most common monogenic dystonia characterized by involuntary muscle contractions and lack of therapeutic options. Despite some insights into its etiology, the disease’s pathophysiology remains unclear. The reduced penetrance of about 30% suggests that extragenetic factors are needed to develop a dystonic phenotype. In order to systematically investigate this hypothesis, we induced a sciatic nerve crush injury in a genetically predisposed DYT-TOR1A mouse model (DYT1KI) to evoke a dystonic phenotype. Subsequently, we employed a multi-omic approach to uncover novel pathophysiological pathways that might be responsible for this condition. Using an unbiased deep-learning-based characterization of the dystonic phenotype showed that nerve-injured DYT1KI animals exhibited significantly more dystonia-like movements (DLM) compared to naive DYT1KI animals. This finding was noticeable as early as two weeks following the surgical procedure. Furthermore, nerve injured DYT1KI mice displayed significantly more DLM than nerve-injured wildtype (wt) animals starting at 6 weeks post injury. In the cerebellum of nerve-injured wt mice, multi-omic analysis pointed towards regulation in translation related processes. These observations were not made in the cerebellum of nerve-injured DYT1KI mice; instead, they were localized to the cortex and striatum. Our findings indicate a lack of effective translational rescue mechanisms in the cerebellum of phenotypic DYT1KI mice that exhibit DLM, while translation dysregulations in the cortex and striatum likely contribute to the dystonic phenotype.}, added-at = {2024-02-26T11:31:45.000+0100}, author = {Reinhold, Colette and Knorr, Susanne and McFleder, Rhonda L. and Rauschenberger, Lisa and Muthuraman, Muthuraman and Arampatzi, Panagiota and Gräfenhan, Tom and Schlosser, Andreas and Sendtner, Michael and Volkmann, Jens and Ip, Chi Wang}, biburl = {https://www.bibsonomy.org/bibtex/22f5def6ef28284a60db87502d3372b17/cusysmed}, day = 1, doi = {10.1016/j.nbd.2024.106453}, interhash = {5572d06ea27a38b82b3dbc728722afb2}, intrahash = {2f5def6ef28284a60db87502d3372b17}, issn = {0969-9961}, journal = {Neurobiology of Disease}, keywords = {myown}, month = {3}, pages = 106453, publisher = {Elsevier BV}, timestamp = {2024-04-03T14:08:15.000+0200}, title = {Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model}, url = {http://dx.doi.org/10.1016/j.nbd.2024.106453}, year = 2024 }