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PACT and its murine homolog RAX activate protein kinase R (PKR; also known as EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the \u03b1 subunit of eukaryotic translation initiation factor 2 (eIF2\u03b1). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkralear-5J, exhibit progressive dystonia. In the present study, we investigated the biochemical and developmental consequences of the Prkralear-5J mutation. Our results indicated that the truncated PACT\/RAX protein retains its ability to interact with PKR but inhibits PKR activation. Mice homozygous for the mutation showed abnormalities in cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2\u03b1 phosphorylation was noted in the cerebellum and Purkinje neurons of the homozygous Prkralear-5J mice. These findings 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 the Prkralear-5J mutation.<\/jats:p>","DOI":"10.1242\/dmm.050929","type":"journal-article","created":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T09:08:18Z","timestamp":1731056898000},"source":"Crossref","is-referenced-by-count":6,"title":["Mutation in <i>Prkra<\/i> results in cerebellar abnormality and reduced eIF2\u03b1 phosphorylation in a model of DYT-PRKRA"],"prefix":"10.1242","volume":"17","author":[{"given":"Samuel B.","family":"Burnett","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of South Carolina 1 , Columbia, SC 29208 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison M.","family":"Culver","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of South Carolina 1 , Columbia, SC 29208 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tricia A.","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of South Carolina 1 , Columbia, SC 29208 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Rowson","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of South Carolina 1 , Columbia, SC 29208 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Frederick","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of South Carolina 1 , Columbia, SC 29208 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Palmer","sequence":"additional","affiliation":[{"name":"Genetic Resource Center, The Jackson Laboratory 2 , 600 Main Street, Bar Harbor, ME 04609 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Murray","sequence":"additional","affiliation":[{"name":"Genetic Resource Center, The Jackson Laboratory 2 , 600 Main Street, Bar Harbor, ME 04609 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon W.","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of South Carolina 1 , Columbia, SC 29208 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9434-4880","authenticated-orcid":false,"given":"Rekha C.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of South Carolina 1 , Columbia, SC 29208 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"2024112609295515500_DMM050929C1","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/sj.cdd.4400823","article-title":"Host defense, viruses and apoptosis","volume":"8","author":"Barber","year":"2001","journal-title":"Cell. 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