run_metadata: 10389
This data as json
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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 10389 | ERR8517039 | ERX8083513 | ERS10517670 | ERP135370 | PRJEB50765 | HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS | 69e2093b-755e-4be3-88b8-5b4a761258fe | Other | A 'GGGGCC' repeat expansion in the first intron of the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis ALS and frontotemporal dementia FTD. The exact mechanism resulting in these neurodegenerative diseases remains elusive but RNA toxicity has been implicated as a gain of function mechanism. Our aim was to use a zebrafish model for C9orf72 RNA toxicity to identify modifiers of the ALS linked phenotype. We discovered that the RNA binding protein heterogeneous nuclear ribonucleoprotein K HNRNPK can reverse the toxicity of both sense and antisense repeat RNA which is dependent on its subcellular localization and on RNA recognition and not on C9 repeat RNA binding. We observed HNRNPK cytoplasmic mislocalization in C9orf72 ALS patient fibroblasts induced pluripotent stem cell iPSC derived motor neurons and postmortem central cortex suggesting a disrupted HNRNPK function in C9orf72 ALS. In C9 ALS/FTD patient tissue we discovered an increased nuclear translocation but reduced expression of Ribonucleotide Reductase Regulatory Subunit M2 RRM2 a downstream target of HNRNPK involved in DNA damage response. Finally we show that increasing the expression of HNRNPK or RRM2 was sufficient to mitigate DNA damage in our C9 RNA toxicity zebrafish model. Overall our study strengthens the relevance of RNA toxicity as a pathogenic mechanism in C9 ALS and demonstrates its link with aberrant DNA damage response opening novel therapeutic strategies for C9 ALS/FTD. | ENA FIRST PUBLIC:2022 08 22|ENA LAST UPDATE:2022 08 22 | PUBMED:29302778;PUBMED:35895140 | Toxic condition | 91S GFP 003 | SAMEA12918520 | vib-ku leuven | ENA FIRST PUBLIC:2022 08 22|ENA LAST UPDATE:2022 08 22|External Id:SAMEA12918520|INSDC center alias:VIB KU Leuven|INSDC center name:vib ku leuven|INSDC first public:2022 08 22T12:15:26Z|INSDC last update:2022 08 22T12:15:26Z|INSDC status:public|Submitter Id:91S GFP 003|common name:zebrafish|sample name:91S GFP 003 | NextSeq 500 paired end sequencing; Raw reads: 91S GFP 003 | webin reads 91S GFP 003 | unspecified | RNA-Seq | TRANSCRIPTOMIC | PolyA | PAIRED | ILLUMINA | NextSeq 500 | ERP135370 | Raw reads: 91S GFP 003 | ENA FIRST PUBLIC:2022 08 22|ENA LAST UPDATE:2022 08 22 | 91S_GFP_003_R1.fastq.gz 91S_GFP_003_R2.fastq.gz | fastq fastq | 2946600193.0 | 19521826.0 | webin reads 91S GFP 003 | 0:75.51 1:75.43 | A:763284580;C:704439363;G:702989767;T:775149110;N:737373 | 75 | 75 | 763284580 | 704439363 | 702989767 | 775149110 | 737373 | ERX8083513 | ERS10517670 | ERA8933888 | vib-ku leuven|European Nucleotide Archive | vib-ku leuven | 2 | 0.96151 | 0.96295 | 0.06621 | 0.06481 | 0.68807 | 0.69092 | 0.46928 | 0.46982 | 75 | 76 | B | B | biological fallback assumption | illumina | nextseq | unknown | poly_a | unknown | bulk | unknown | unknown | Belgium | 2022-08-22 | Undetermined | Undetermined | Undetermined | Undetermined |