Abstract
AbstractPIWI-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.
Funder
Universidade de Macau
National Natural Science Foundation of China
Shantou University
Li Ka Shing Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Cited by
1 articles.
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