Molecular basis of neurodegeneration in a mouse model of Polr3-related disease (tRNA)
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PROVIDER: PRJNA1031687 | ENA |
REPOSITORIES: ENA
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Project description:Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of neurodegenerative diseases including 4H leukodystrophy. We developed a postnatal whole-body mouse model expressing pathogenic mutations in Polr3a to examine the molecular mechanisms by which reduced Pol III activity results primarily in central nervous system phenotypes. Polr3a mutant mice exhibit behavioral deficits, exocrine pancreatic atrophy and cerebral pathology. Transcriptome and immunohistochemistry analyses of cerebra show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. A global decrease in mature tRNA levels and an altered tRNA profile preceded cerebral neurodegeneration suggesting a causal role in disease initiation. In cerebella, heart and kidney, Pol III transcripts other than tRNAs were generally unaffected. The results suggest tissue-specific thresholds of sensitivity to defects in Pol III transcription.
2024-01-10 | GSE246161 | GEO
Project description:Molecular basis of neurodegeneration in a mouse model of Polr3-related disease
| PRJNA1031683 | ENA
Project description:Molecular basis of neurodegeneration in a mouse model of Polr3-related disease (RNA)
| PRJNA1031685 | ENA
Project description:Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of neurodegenerative diseases including 4H leukodystrophy. We developed a postnatal whole-body mouse model expressing pathogenic mutations in Polr3a to examine the molecular mechanisms by which reduced Pol III activity results primarily in central nervous system phenotypes. Polr3a mutant mice exhibit behavioral deficits, exocrine pancreatic atrophy and cerebral pathology. Transcriptome and immunohistochemistry analyses of cerebra show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. A global decrease in mature tRNA levels and an altered tRNA profile preceded cerebral neurodegeneration suggesting a causal role in disease initiation. In cerebella, heart and kidney, Pol III transcripts other than tRNAs were generally unaffected. The results suggest tissue-specific thresholds of sensitivity to defects in Pol III transcription.
2024-01-10 | GSE246160 | GEO
Project description:In higher eukaryotes, the large numbers of nuclear-encoded tRNA genes partially ensure the robustness of cytoplasmic protein translation. Here we discover that a loss-of-function in n-Tr20, a member of the nuclear-encoded tRNA Arg UCU family that is expressed specifically in the central nervous systems leads to low but detectable levels of ribosome stalling. In the absence of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, ribosome stalling increases, leading to widespread neurodegeneration. Our results not only define GTPBP2 as a ribosome rescue factor, but also unmask the disease potential of mutations in nuclear-encoded tRNA genes. In this submission we provide ribosome footprinting data from the cerebella of four strains derived from the C57BL/6J strain with combinations of n-Tr20 and GTPBP2 mutations. Examination of ribosome stalling in cerebella from 4 mouse strains derived from the: C57BL/6J (B6J) strain. The nmf205-/- strain has a homozygous mutation in the gene GTPBP2 while the B6J strain has normal GTPBP2. The n-Tr20 J/J strain has a defect in the n-Tr20 tRNA while the n-Tr20 N/N strain has a functional n-Tr20 tRNA. The 4 strains are the 2x2 combinations of these defects and correctly functioning sequences. 2 replicates for each strain. Please note that only BAM files are included in the records since they form the basis of the study's conclusions. The raw data ribosomal RNA have been filtered and then unique reads mapping to mm10 were computed using tophat and igenome annotations.
2014-07-28 | E-GEOD-56127 | biostudies-arrayexpress
Project description:Pseudouridine (Ψ), the isomer of uridine, is ubiquitous in most RNA families, including tRNA, rRNA and mRNA. Pseudouridine synthase 3 (PUS3) catalyzes pseudouridylation of position 38/39 in tRNAs, but whether it can modify other RNA types, including mRNA, remains elusive. Here, we determine the single particle cryo-EM structure of apo and tRNA-bound human PUS3, showing how it forms a symmetric homodimer that recognizes the characteristic L-shape of tRNA across two distinct interaction interfaces. Structure-guided and patient-derived mutations validate our structural findings in complementary biochemical assays. Furthermore, we deleted PUS1 and PUS3 in HEK293 cells and used Pseudo-seq to detect Ψ sites in the transcriptome. Although PUS1-dependent sites were detectable in tRNA and mRNA, we did not find any evidence for PUS3 modifying other RNA classes than tRNA. In summary, our work provides the molecular basis for PUS3-mediated tRNA modification in humans and aids in understanding how impairments in its activity lead to intellectual disabilities through defects in tRNA modifications.
2024-07-10 | GSE255287 | GEO
Project description:In higher eukaryotes, the large numbers of nuclear-encoded tRNA genes partially ensure the robustness of cytoplasmic protein translation. Here we discover that a loss-of-function in n-Tr20, a member of the nuclear-encoded tRNA Arg UCU family that is expressed specifically in the central nervous systems leads to low but detectable levels of ribosome stalling. In the absence of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, ribosome stalling increases, leading to widespread neurodegeneration. Our results not only define GTPBP2 as a ribosome rescue factor, but also unmask the disease potential of mutations in nuclear-encoded tRNA genes. In this submission we provide ribosome footprinting data from the cerebella of four strains derived from the C57BL/6J strain with combinations of n-Tr20 and GTPBP2 mutations.
2014-07-28 | GSE56127 | GEO
Project description:The molecular basis of tRNA selectivity by human pseudouridine synthase 3 (PUS3)
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2024-01-10 | GSE246162 | GEO
Project description:cGAS/STING drives ageing-related inflammation and neurodegeneration
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