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Additional file 1.

Supplementary material for "A heterozygous mutation in in CCDC88C gene causes early onset pure hereditary spastic paraplegia".

Polyglutamine (polyQ) diseases represent a group of progressive neurodegenerative disorders that are caused by abnormal expansion of CAG triplet nucleotides in disease genes. Recent evidence indicates that not only mutant polyQ proteins, but also their corresponding mutant RNAs, contribute to the pathogenesis of polyQ diseases. Here, we describe the identification of a 13-amino-acid peptide, P3, which binds directly and preferentially to long-CAG RNA within the pathogenic range. When administered to cell and Drosophila disease models, as well as to patient-derived fibroblasts, P3 inhibited expanded-CAG-RNA-induced nucleolar stress and suppressed neurotoxicity. We further examined the combined therapeutic effect of P3 and polyQ-binding peptide 1 (QBP1), a well-characterized polyQ protein toxicity inhibitor, on neurodegeneration. When P3 and QBP1 were co-administered to disease models, both RNA and protein toxicities were effectively mitigated, resulting in a notable improvement of neurotoxicity suppression compared with the P3 and QBP1 single-treatment controls. Our findings indicate that targeting toxic RNAs and/or simultaneous targeting of toxic RNAs and their corresponding proteins could open up a new therapeutic strategy for treating polyQ degeneration., Drosophila Collection: We identified a novel peptidylic inhibitor against expanded CAG RNA toxicity. Our study highlights the importance of simultaneously targeting both toxic RNA and protein species in treating polyQ degeneration.

Arthropods comprise the majority of all described animal species, and understanding their evolution is a central question in biology. Their developmental processes are under the precise control of distinct hormonal regulators, including the sesquiterpenoids juvenile hormone (JH) and methyl farnesoate (MF). The control of the synthesis and mode of action of these hormones played important roles in the evolution of arthropods and their adaptation to diverse habitats. However, the precise roles of non-coding RNAs, such as microRNAs, controlling arthropod hormonal pathways are unknown. Here, we investigated the microRNA regulation of the expression of the juvenile hormone acid methyltransferase gene (JHAMT), which encodes a rate-determining sesquiterpenoid biosynthetic enzyme. Loss of function of the microRNA bantam in the fly Drosophila melanogaster increased JHAMT expression, while overexpression of the bantam repressed JHAMT expression and resulted in pupal lethality. The male genital organs of the pupae were malformed, and exogenous sesquiterpenoid application partially rescued the genital deformities. The role of the bantam in the regulation of sesquiterpenoid biosynthesis was validated by transcriptomic, qPCR and hormone titre (JHB3 and JH III) analyses. In addition, we found a conserved set of microRNAs that interacted with JHAMT, and the sesquiterpenoid receptor Methoprene-tolerant (Met) in different arthropod lineages, including insects (fly, mosquito and beetle), crustaceans (water flea and shrimp), myriapod (centipede) and chelicerate (horseshoe crab). This suggests that these microRNAs might have conserved roles in the post-transcriptional regulation of genes in sesquiterpenoid pathways across the Panarthropoda. Some of the identified lineage-specific microRNAs are potential targets for the development of new strategies in aquaculture and agricultural pest control.

Arthropods comprise the majority of all described animal species, and understanding their evolution is a central question in biology. Their developmental processes are under the precise control of distinct hormonal regulators, including the sesquiterpenoids juvenile hormone (JH) and methyl farnesoate (MF). The control of the synthesis and mode of action of these hormones played important roles in the evolution of arthropods and their adaptation to diverse habitats. However, the precise roles of non-coding RNAs, such as microRNAs, controlling arthropod hormonal pathways are unknown. Here, we investigated the microRNA regulation of the expression of the juvenile hormone acid methyltransferase gene (JHAMT), which encodes a rate-determining sesquiterpenoid biosynthetic enzyme. Loss of function of the microRNA bantam in the fly Drosophila melanogaster increased JHAMT expression, while overexpression of the bantam repressed JHAMT expression and resulted in pupal lethality. The male genital organs of the pupae were malformed, and exogenous sesquiterpenoid application partially rescued the genital deformities. The role of the bantam in the regulation of sesquiterpenoid biosynthesis was validated by transcriptomic, qPCR and hormone titre (JHB3 and JH III) analyses. In addition, we found a conserved set of microRNAs that interacted with JHAMT, and the sesquiterpenoid receptor Methoprene-tolerant (Met) in different arthropod lineages, including insects (fly, mosquito and beetle), crustaceans (water flea and shrimp), myriapod (centipede) and chelicerate (horseshoe crab). This suggests that these microRNAs might have conserved roles in the post-transcriptional regulation of genes in sesquiterpenoid pathways across the Panarthropoda. Some of the identified lineage-specific microRNAs are potential targets for the development of new strategies in aquaculture and agricultural pest control.

Arthropods comprise the majority of all described animal species, and understanding their evolution is a central question in biology. Their developmental processes are under the precise control of distinct hormonal regulators, including the sesquiterpenoids juvenile hormone (JH) and methyl farnesoate (MF). The control of the synthesis and mode of action of these hormones played important roles in the evolution of arthropods and their adaptation to diverse habitats. However, the precise roles of non-coding RNAs, such as microRNAs, controlling arthropod hormonal pathways are unknown. Here, we investigated the microRNA regulation of the expression of the juvenile hormone acid methyltransferase gene (JHAMT), which encodes a rate-determining sesquiterpenoid biosynthetic enzyme. Loss of function of the microRNA bantam in the fly Drosophila melanogaster increased JHAMT expression, while overexpression of the bantam repressed JHAMT expression and resulted in pupal lethality. The male genital organs of the pupae were malformed, and exogenous sesquiterpenoid application partially rescued the genital deformities. The role of the bantam in the regulation of sesquiterpenoid biosynthesis was validated by transcriptomic, qPCR and hormone titre (JHB3 and JH III) analyses. In addition, we found a conserved set of microRNAs that interacted with JHAMT, and the sesquiterpenoid receptor Methoprene-tolerant (Met) in different arthropod lineages, including insects (fly, mosquito and beetle), crustaceans (water flea and shrimp), myriapod (centipede) and chelicerate (horseshoe crab). This suggests that these microRNAs might have conserved roles in the post-transcriptional regulation of genes in sesquiterpenoid pathways across the Panarthropoda. Some of the identified lineage-specific microRNAs are potential targets for the development of new strategies in aquaculture and agricultural pest control.