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

Xiaobing Huang, Changliang Wang, Tianjiao Zhang, Rongzhen Li, Liang Chen, Ka Lai Leung, Merja Lakso, Qinghua Zhou, Hongjie Zhang and Garry Wong ()
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Xiaobing Huang: Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University
Changliang Wang: University of Macau
Tianjiao Zhang: University of Macau
Rongzhen Li: University of Macau
Liang Chen: Shantou University
Ka Lai Leung: University of Macau
Merja Lakso: University of Macau
Qinghua Zhou: Jinan University
Hongjie Zhang: University of Macau
Garry Wong: University of Macau

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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)Tg and AβTg;α-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 α-syn(A53T)Tg and AβTg;α-syn(A53T)Tg transgenic strains. piRNA expression was extensively downregulated and H3K9me3 marks were decreased after tofu-1 deletion in α-syn(A53T)Tg and AβTg;α-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.

Date: 2023
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DOI: 10.1038/s41467-023-41881-8

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