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bioRxiv · 10.1101/2024.06.04.597421

A frameshift mutation in the murine Prkra gene causes dystonia and exhibits abnormal cerebellar development and reduced eIF2α phosphorylation.

Burnett, S. B.·Culver, A. M.·Simon, T. A.·Rowson, T.·Frederick, K.·Palmer, K.·Murray, S.·Davis, S. W.·Patel, R. C.
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Abstract

Mutations in Prkra gene, which encodes PACT/RAX cause early onset primary dystonia DYT-PRKRA, a movement disorder that disrupts coordinated muscle movements. PACT/RAX activates protein kinase R (PKR, aka EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the subunit of the eukaryotic translation initiation factor 2 (eIF2). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkralear-5J exhibit progressive dystonia. In the present study, we investigate the biochemical and developmental consequences of the Prkralear-5J mutation. Our results indicate that the truncated PACT/RAX protein retains its ability to interact with PKR, however, it inhibits PKR activation. Furthermore, mice homozygous for the mutation have abnormalities in the cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2 phosphorylation is noted in the cerebellums and Purkinje neurons of the homozygous Prkralear-5J mice. These results indicate that PACT/RAX mediated regulation of PKR activity and eIF2 phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation. Summary StatementThis study shows, for the first time, a role of reduced eIF2 phosphorylation in DYT-PRKRA and the cerebellum development in a mouse model.

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Burnett, S. B., Culver, A. M., Simon, T. A., Rowson, T., Frederick, K., Palmer, K., Murray, S., Davis, S. W., Patel, R. C.. 2024-06-04. A frameshift mutation in the murine Prkra gene causes dystonia and exhibits abnormal cerebellar development and reduced eIF2α phosphorylation.. https://doi.org/10.1101/2024.06.04.597421

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