Objective: Our overall objective was to investigate the involvement of type I interferons (IFNs) in DYT-PRKRAand DYT-EIF2AK2. IFNs are antiviral cytokines produced by all cell types in response to viral infections.

Background: DYT-PRKRA (aka DYT16) is caused by mutations in the PRKRA gene, encoding PACT, a protein activator of the IFN-induced protein kinase (PKR). DYT-EIF2AK2 (aka DYT33) is caused by mutations in the EIF2AK2 gene encoding IFN-induced protein kinase EIF2AK2 (aka PKR). PKR is ubiquitously expressed and is induced at transcriptional level by IFNs but needs binding to its activator for a conformational change leading to its catalytic activation. In virally infected cells, double-stranded RNA (dsRNA) activates PKR and in the absence of viral infections, PACT activates PKR in response to non-viral cellular stress. Activated PKR phosphorylates the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2alpha), leading to a block in protein synthesis and inhibiting viral replication. PACT and PKR are both known to be involved in the induction of IFNs in response to viral infections.

Method: We compared the response of DYT-PKKRA and DYT-EIF2AK2 patient cells and their wt counterparts to dsRNA, a viral mimic . The cells were treated with dsRNA and the effects on PKR induction, activation, expression of IFN-induced genes (ISGs) and cell apoptosis were analysed using western blot, qRTPCR analyses and caspase 3/7 activity assays.

Results: The DYT-EIF2AK2 cells show a heightened induction as well as activation of PKR, which triggers enhanced apoptosis after dsRNA treatment. The DYT-PRKRA lymphoblasts showed higher expression of ISGs compared to the wild type controls. Furthermore, both DYT-PRKRA and DYT-EIF2AK2 cells showed enhanced apoptosis in response to IFN and dsRNA.

Conclusion: These findings provide a critical novel insight into the molecular mechanism for DYT-PPKRA and DYT-EIF2AK2suggesting a connection between the onset of dystonia after a childhood febrile illness. Based on further research, targeting excessive IFN induction, inhibiting PKR activation or downstream pro-apoptotic pathways could offer novel therapeutic avenues to mitigate this movement disorder in patients.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/molecular-studies-reveal-overactive-interferon-ifn-pathway-in-two-monogenic-inherited-dystonia-types/