Document Type

Article

Publication Date

11-1-2024

Keywords

JMG, Animals, Phosphorylation, Eukaryotic Initiation Factor-2, Cerebellum, Disease Models, Animal, Mutation, eIF-2 Kinase, Purkinje Cells, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Mice, Enzyme Activation, Humans, Homozygote, Dystonia Musculorum Deformans, Dendrites

ISSN

1754-8411

PMID

39512178

DOI

https://doi.org/10.1242/dmm.050929

Grant

the National Institutes of Health (DE020052 to S.A.M.)

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.

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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