Mutation in Prkra results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA

• Published in: Disease models & mechanisms 2024-11, Vol.17 (11)
• Main Authors: Burnett, Samuel B, Culver, Allison M, Simon, Tricia A, Rowson, Taylor, Frederick, Kenneth, Palmer, Kristina, Murray, Stephen A, Davis, Shannon W, Patel, Rekha C
• Format: Article
• Language: English
• Subjects: Animals; cerebellum; Cerebellum - abnormalities; Cerebellum - metabolism; Cerebellum - pathology; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - genetics; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - metabolism; Dendrites - metabolism; Disease Models, Animal; dystonia; Dystonia Musculorum Deformans - genetics; Dystonia Musculorum Deformans - metabolism; dyt-prkra; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; eif2ak2; Enzyme Activation; Eukaryotic Initiation Factor-2 - metabolism; Homozygote; Humans; Mice; Mutation - genetics; pact/rax; Phosphorylation; pkr; Purkinje Cells - metabolism; Purkinje Cells - pathology
• ISSN: 1754-8403; 1754-8411; 1754-8411
• DOI: 10.1242/dmm.050929

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.