{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:19:49Z","timestamp":1768511989239,"version":"3.49.0"},"posted":{"date-parts":[[2024,6,4]]},"group-title":"Molecular Biology","reference-count":86,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Mutations in\n                  <jats:italic>Prkra<\/jats:italic>\n                  gene, which encodes PACT\/RAX cause early onset primary dystonia DYT-PRKRA, a movement disorder that disrupts coordinated muscle movements. PACT\/RAX activates protein kinase R (PKR, aka EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the \u03b1 subunit of the eukaryotic translation initiation factor 2 (eIF2\u03b1). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation,\n                  <jats:italic>\n                    Prkra\n                    <jats:sup>lear-5J<\/jats:sup>\n                  <\/jats:italic>\n                  exhibit progressive dystonia. In the present study, we investigate the biochemical and developmental consequences of the\n                  <jats:italic>\n                    Prkra\n                    <jats:sup>lear-5J<\/jats:sup>\n                  <\/jats:italic>\n                  mutation. Our results indicate that the truncated PACT\/RAX protein retains its ability to interact with PKR, however, it inhibits PKR activation. Furthermore, mice homozygous for the mutation have abnormalities in the cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2\u03b1 phosphorylation is noted in the cerebellums and Purkinje neurons of the homozygous\n                  <jats:italic>\n                    Prkra\n                    <jats:sup>lear-5J<\/jats:sup>\n                  <\/jats:italic>\n                  mice. These results indicate that PACT\/RAX mediated regulation of PKR activity and eIF2\u03b1 phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary Statement<\/jats:title>\n                  <jats:p>This study shows, for the first time, a role of reduced eIF2\u03b1 phosphorylation in DYT-PRKRA and the cerebellum development in a mouse model.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.06.04.597421","type":"posted-content","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:15:19Z","timestamp":1717546519000},"source":"Crossref","is-referenced-by-count":2,"title":["A frameshift mutation in the murine\n                  <i>Prkra<\/i>\n                  gene causes dystonia and exhibits abnormal cerebellar development and reduced eIF2\u03b1 phosphorylation"],"prefix":"10.64898","author":[{"given":"Samuel B.","family":"Burnett","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison M.","family":"Culver","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tricia A.","family":"Simon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taylor","family":"Rowson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth","family":"Frederick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen A","family":"Murray","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon W.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rekha C.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024060713300447000_2024.06.04.597421v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400823"},{"key":"2024060713300447000_2024.06.04.597421v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2017.12.033"},{"issue":"10","key":"2024060713300447000_2024.06.04.597421v1.3","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/cm.21294","article-title":"Translational control by eIF2\u03b1 in neurons: Beyond the stress response","volume":"73","year":"2016","journal-title":"Cytoskeleton (Hoboken)"},{"key":"2024060713300447000_2024.06.04.597421v1.4","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.3.611"},{"key":"2024060713300447000_2024.06.04.597421v1.5","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-11-006817"},{"key":"2024060713300447000_2024.06.04.597421v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2008.06.009"},{"key":"2024060713300447000_2024.06.04.597421v1.7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403321200"},{"issue":"5","key":"2024060713300447000_2024.06.04.597421v1.8","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1212\/WNL.0000000000200858","article-title":"Early-Onset Dystonia, Exacerbation With Fever, and Striatal Signal Changes: Emerging Phenotype of DYT-PRKRA","volume":"99","year":"2022","journal-title":"Neurology"},{"key":"2024060713300447000_2024.06.04.597421v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-64189-2.00017-2"},{"key":"2024060713300447000_2024.06.04.597421v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2010.11.015"},{"key":"2024060713300447000_2024.06.04.597421v1.11","doi-asserted-by":"crossref","first-page":"105135","DOI":"10.1016\/j.nbd.2020.105135","article-title":"Dystonia 16 (DYT16) mutations in PACT cause dysregulated PKR activation and eIF2\u03b1 signaling leading to a compromised stress response","volume":"146","year":"2020","journal-title":"Neurobiol Dis"},{"issue":"11","key":"2024060713300447000_2024.06.04.597421v1.12","doi-asserted-by":"crossref","first-page":"19004","DOI":"10.1002\/jcb.29223","article-title":"A truncated PACT protein resulting from a frameshift mutation reported in movement disorder DYT16 triggers caspase activation and apoptosis","volume":"120","year":"2019","journal-title":"J Cell Biochem"},{"key":"2024060713300447000_2024.06.04.597421v1.13","doi-asserted-by":"crossref","unstructured":"Caffall, Z. 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