PIWI-interacting RNA expression regulates pathogenesis in a Caenorhabditis elegans model of Lewy body disease

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 alpha-syn(A53T)Tg and A beta Tg;alpha-syn(A53T)Tg 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 alpha-syn(A53T)Tg and A beta Tg;alpha-syn(A53T)Tg transgenic strains. piRNA expression was extensively downregulated and H3K9me3 marks were decreased after tofu-1 deletion in alpha-syn(A53T)Tg and A beta Tg;alpha-syn(A53T)Tg 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.

Automated summary

PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that play important roles in regulating gene expression and neurodegeneration. This study found dysregulated expression of piRNAs in disease models and brain samples of Parkinson's disease patients, suggesting their involvement in the pathogenesis of Lewy body diseases. The results provide insights into the molecular mechanisms underlying neurodegenerative disorders.