{"doi":"10.1242/dmm.050929","title":"Mutation in <i>Prkra</i> results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA","abstract":"Variants in the PRKRA gene, which encodes PACT, cause the early-onset primary dystonia DYT-PRKRA, a movement disorder associated with disruption of coordinated muscle movements. 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 α subunit of eukaryotic translation initiation factor 2 (eIF2α). 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 eIF2α 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 eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from the Prkralear-5J mutation.","journal":"Disease Models & Mechanisms","year":2024,"id":458740,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9485,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1285522,"name":"Allison M. Culver","orcid":null,"position":1,"is_corresponding":false},{"id":1285523,"name":"Tricia A. Simon","orcid":null,"position":2,"is_corresponding":false},{"id":1285524,"name":"Taylor Rowson","orcid":null,"position":3,"is_corresponding":false},{"id":1107888,"name":"Kenneth Frederick","orcid":null,"position":4,"is_corresponding":false},{"id":916232,"name":"Kristina Palmer","orcid":null,"position":5,"is_corresponding":false},{"id":266971,"name":"Stephen A. Murray","orcid":"0000-0002-0594-1702","position":6,"is_corresponding":false},{"id":584159,"name":"Shannon W. Davis","orcid":"0000-0001-7354-5691","position":7,"is_corresponding":false},{"id":909496,"name":"Rekha C. Patel","orcid":"0000-0001-9434-4880","position":8,"is_corresponding":false},{"id":1285521,"name":"Samuel B. Burnett","orcid":null,"position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":null,"created_at":"2026-07-19T02:03:50.608887Z","pmid":"39512178","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}