Zhai, S.-N. | bioRxiv Science

bioRxiv2024

Circular RNA aptamers ameliorate AD-relevant phenotypes by targeting PKR

Here, we delineated the remarkably elevated neuroinflammation accompanied by progressive activation of double-stranded RNA (dsRNA)-activated Protein Kinase R (PKR) and PKR-related dsRNA pathways in hippocampus of 5xFAD mice upon Alzheimers disease (AD) progression. AAV-delivery of circular RNAs possessing short-imperfect duplex regions (ds-cRNAs) to neurons and microglia effectively dampened excessive PKR activity with little toxicity, accompanying with reduced neuroinflammation and amyloid-beta (A{beta}) plaques, resulting in neuroprotection and enhanced capability of spatial learning and memory in AD mouse models. These findings suggest a therapeutic potential of ds-cRNA aptamers as PKR inhibitors in AD therapy.

molecular biology↗

bioRxiv2023

IntS6 and the Integrator phosphatase module tune the efficiency of select premature transcription termination events

The metazoan-specific Integrator complex catalyzes 3 end processing of small nuclear RNAs (snRNAs) as well as premature transcription termination events that attenuate expression of many protein-coding genes. Integrator has RNA endonuclease and protein phosphatase activities, but it remains unclear if both are always required for complex function. Here, we show that IntS6 (Integrator subunit 6) over-expression is sufficient to block Integrator function at a subset of Drosophila protein-coding genes, while having no effect on snRNA processing or attenuation of other loci. Over-expressed IntS6 titrates protein phosphatase 2A (PP2A) subunits from the rest of the Integrator complex and thus the only loci affected are those where the phosphatase module is necessary for Integrator function. IntS6 functions analogous to a PP2A regulatory B subunit as over-expression of canonical B subunits, which do not associate with Integrator, are also sufficient to inhibit Integrator function at select loci. Altogether, these results show that the phosphatase module is critical and limiting at only a subset of Integrator regulated genes and point to recruitment of PP2A via IntS6 as a tunable step that can be used to modulate transcription termination efficiency.

molecular biology↗