Dystonia is a movement disorder involving sustained muscle contractions, which can lead to painful, twisting, repetitive movements and abnormal postures. Although several dystonia-causing variants have been identified in various genes, the underlying pathological molecular mechanisms for most dystonia types remain unknown.

 DYT-PRKRA [also known as dystonia 16 (DYT16)] is an early-onset generalized dystonia characterized by progressive limb dystonia, laryngeal and oromandibular dystonia and parkinsonism. It is caused by variants in the PRKRA gene, which encodes the protein PACT, a stress-modulated activator of the protein kinase PKR. PKR is one of the four protein kinases that regulate the integrated stress response (ISR), an evolutionarily conserved pathway activated by a diverse set of stress signals in eukaryotic cells to restore cellular homeostasis. Studies on DYT-PRKRA patient-derived lymphoblasts have revealed that DYT-PRKRA PACT variants increase cellular susceptibility to stress due to dysregulated stress response signaling.

Like DYT-PRKRA patients having PACT variants, mice homozygous for a spontaneous recessively inherited frameshift mutation (lear-5J) in the murine Prkra gene exhibit progressive dystonia. Mutant mice present with craniofacial developmental abnormalities, small ear size, drastically reduced body size, kinked tails, and ascending dystonia that progresses until becoming fatal at 3-6 weeks of age. In their new study titled "Mutation in Prkra results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA", the Patel and Davis labs, including three graduate students from Patel lab and one graduate student from Davis lab, undertook an initial characterization of the in vitro and in vivo consequences of the lear-5J mutation in mice.  They found that the truncated PACT protein generated in mutant mice retains its ability to interact with PKR but inhibits PKR activation., and that mutant mice show abnormalities in cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons (as illustrated in figure). These findings indicate that PACT-mediated regulation of PKR activity plays a role in cerebellar development and contributes to the dystonia phenotype resulting from the lear-5J mutation.