A frameshift mutation in the murine Prkra gene exhibits cerebellar abnormality and reduced eIF2α phosphorylation.
| Autor: | Burnett SB; University of South Carolina, SC 29208, Columbia., Culver AM; University of South Carolina, SC 29208, Columbia., Simon TA; University of South Carolina, SC 29208, Columbia., Rowson T; University of South Carolina, SC 29208, Columbia., Frederick K; University of South Carolina, SC 29208, Columbia., Palmer K; The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA., Murray SA; The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA., Davis SW; University of South Carolina, SC 29208, Columbia., Patel RC; University of South Carolina, SC 29208, Columbia. |
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| Jazyk: | angličtina |
| Zdroj: | Disease models & mechanisms [Dis Model Mech] 2024 Nov 08. Date of Electronic Publication: 2024 Nov 08. |
| DOI: | 10.1242/dmm.050929 |
| Abstrakt: | 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 α subunit of the 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 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 eIF2α 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 eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation. (© 2024. Published by The Company of Biologists Ltd.) |
| Databáze: | MEDLINE |
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