Alternative 3′ UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD
Abstract Recent research has highlighted widespread dysregulation of alternative polyadenylation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Here, we identify significant disruptions to 3` UTR polyadenylation in the ALS/FTLD-TDP mous...
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BMC
2025-01-01
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| Series: | Molecular Brain |
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| Online Access: | https://doi.org/10.1186/s13041-025-01174-1 |
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| author | Randall J. Eck Paul N. Valdmanis Nicole F. Liachko Brian C. Kraemer |
| author_facet | Randall J. Eck Paul N. Valdmanis Nicole F. Liachko Brian C. Kraemer |
| author_sort | Randall J. Eck |
| collection | DOAJ |
| description | Abstract Recent research has highlighted widespread dysregulation of alternative polyadenylation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Here, we identify significant disruptions to 3` UTR polyadenylation in the ALS/FTLD-TDP mouse model rNLS8 that correlate with changes in gene expression and protein levels through the re-analysis of published RNA sequencing and proteomic data. A subset of these changes are shared with TDP-43 knock-down mice suggesting depletion of endogenous mouse TDP-43 is a contributor to polyadenylation dysfunction in rNLS8 mice. Some conservation exists between alternative polyadenylation in rNLS8 mice and human disease models including in disease relevant genes and biological pathways. Together, these findings support both TDP-43 loss and toxic gain-of-function phenotypes as contributors to the neurodegeneration in rNLS8 mice, nominating its continued utility as a preclinical model for investigating mechanisms of neurodegeneration in ALS/FTLD-TDP. |
| format | Article |
| id | doaj-art-b5e896fddc474b07800ff7c2b7f1564a |
| institution | Kabale University |
| issn | 1756-6606 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj-art-b5e896fddc474b07800ff7c2b7f1564a2025-01-19T12:43:34ZengBMCMolecular Brain1756-66062025-01-011811610.1186/s13041-025-01174-1Alternative 3′ UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLDRandall J. Eck0Paul N. Valdmanis1Nicole F. Liachko2Brian C. Kraemer3Graduate Program in Neuroscience, University of WashingtonDepartment of Genome Sciences, University of WashingtonDivision of Gerontology and Geriatric Medicine, Department of Medicine, University of WashingtonGraduate Program in Neuroscience, University of WashingtonAbstract Recent research has highlighted widespread dysregulation of alternative polyadenylation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Here, we identify significant disruptions to 3` UTR polyadenylation in the ALS/FTLD-TDP mouse model rNLS8 that correlate with changes in gene expression and protein levels through the re-analysis of published RNA sequencing and proteomic data. A subset of these changes are shared with TDP-43 knock-down mice suggesting depletion of endogenous mouse TDP-43 is a contributor to polyadenylation dysfunction in rNLS8 mice. Some conservation exists between alternative polyadenylation in rNLS8 mice and human disease models including in disease relevant genes and biological pathways. Together, these findings support both TDP-43 loss and toxic gain-of-function phenotypes as contributors to the neurodegeneration in rNLS8 mice, nominating its continued utility as a preclinical model for investigating mechanisms of neurodegeneration in ALS/FTLD-TDP.https://doi.org/10.1186/s13041-025-01174-1ALSFTLDTDP-43Alternative polyadenylation |
| spellingShingle | Randall J. Eck Paul N. Valdmanis Nicole F. Liachko Brian C. Kraemer Alternative 3′ UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD Molecular Brain ALS FTLD TDP-43 Alternative polyadenylation |
| title | Alternative 3′ UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD |
| title_full | Alternative 3′ UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD |
| title_fullStr | Alternative 3′ UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD |
| title_full_unstemmed | Alternative 3′ UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD |
| title_short | Alternative 3′ UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD |
| title_sort | alternative 3 utr polyadenylation is disrupted in the rnls8 mouse model of als ftld |
| topic | ALS FTLD TDP-43 Alternative polyadenylation |
| url | https://doi.org/10.1186/s13041-025-01174-1 |
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