Document Type
Article
Publication Date
11-1-2024
Original Citation
Burnett S,
Culver A,
Simon T,
Rowson T,
Frederick K,
Palmer K,
Murray SA,
Davis S,
Patel R.
Mutation in Prkra results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA. Dis Model Mech. 2024; 17(11):
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.
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