Mutation in Prkra Results in Cerebellar Abnormality and Reduced elF2α Phosphorylation in a Model Of DYT-PRKRA

Author(s)

Samuel B. Burnett
Allison M. Culver
Tricia A. Simon
Taylor Rowson
Kenneth Frederick
Kristina Palmer
Stephen A. Murray
Shannon W. Davis, University of South CarolinaFollow

Document Type

Article

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, Prkra^lear-5J, exhibit progressive dystonia. In the present study, we investigated the biochemical and developmental consequences of the Prkra^lear-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 Prkra^lear-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 Prkra^lear-5J mutation.

Digital Object Identifier (DOI)

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

Publication Info

Published in Disease Models & Mechanisms, Volume 17, Issue 11, 2024.

Rights

© 2024. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

APA Citation

Burnett, S. B., Culver, A. M., Simon, T. A., Rowson, T., Frederick, K., Palmer, K., Murray, S. A., Davis, S. W., & Patel, R. C. (2024). Mutation in Prkra results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA. Disease Models & Mechanisms, 17(11).https://doi.org/10.1242/dmm.050929