PIWI-interacting RNA expression regulates pathogenesis in a Caenorhabditis elegans model of Lewy body disease.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37783675.
- Also identified by DOI 10.1038/s41467-023-41881-8 and PMC identifier 10545829.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that regulate gene expression, yet their molecular functions in neurobiology are unclear. While investigating neurodegeneration mechanisms using human α-syn(A53T)<sup>Tg</sup> and Aβ<sup>Tg</sup>;α-syn(A53T)<sup>Tg</sup> pan-neuronal overexpressing strains, we unexpectedly observed dysregulation of piRNAs. RNAi screening revealed that knock down of piRNA biogenesis genes improved thrashing behavior; further, a tofu-1 gene deletion ameliorated phenotypic deficits in α-syn(A53T)<sup>Tg</sup> and Aβ<sup>Tg</sup>;α-syn(A53T)<sup>Tg</sup> transgenic strains. piRNA expression was extensively downregulated and H3K9me3 marks were decreased after tofu-1 deletion in α-syn(A53T)<sup>Tg</sup> and Aβ<sup>Tg</sup>;α-syn(A53T)<sup>Tg</sup> strains. Dysregulated piRNAs targeted protein degradation genes suggesting that a decrease of piRNA expression leads to an increase of degradation ability in C. elegans. Finally, we interrogated piRNA expression in brain samples from PD patients. piRNAs were observed to be widely overexpressed at late motor stage. In this work, our results provide evidence that piRNAs are mediators in pathogenesis of Lewy body diseases and suggest a molecular mechanism for neurodegeneration in these and related disorders.
Medical subject headings
- Lewy Body Disease
- Caenorhabditis elegans Proteins