The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD
Abstract Expanded intronic G4C2 repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
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Nature Portfolio
2024-03-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-06071-2 |
| _version_ | 1797233414543245312 |
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| author | M. E. Cicardi V. Kankate S. Sriramoji K. Krishnamurthy S. S. Markandaiah B. M. Verdone A. Girdhar A. Nelson L. B. Rivas A. Boehringer A. R. Haeusler P. Pasinelli L. Guo D. Trotti |
| author_facet | M. E. Cicardi V. Kankate S. Sriramoji K. Krishnamurthy S. S. Markandaiah B. M. Verdone A. Girdhar A. Nelson L. B. Rivas A. Boehringer A. R. Haeusler P. Pasinelli L. Guo D. Trotti |
| author_sort | M. E. Cicardi |
| collection | DOAJ |
| description | Abstract Expanded intronic G4C2 repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapβ2 is detrimental to their survival, whereas increased Kapβ2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapβ2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapβ2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD. |
| first_indexed | 2024-04-24T16:15:48Z |
| format | Article |
| id | doaj.art-b72bdbd19e0042fc863c148adeca4f6b |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-04-24T16:15:48Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-b72bdbd19e0042fc863c148adeca4f6b2024-03-31T11:29:11ZengNature PortfolioCommunications Biology2399-36422024-03-017111410.1038/s42003-024-06071-2The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTDM. E. Cicardi0V. Kankate1S. Sriramoji2K. Krishnamurthy3S. S. Markandaiah4B. M. Verdone5A. Girdhar6A. Nelson7L. B. Rivas8A. Boehringer9A. R. Haeusler10P. Pasinelli11L. Guo12D. Trotti13Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityDepartment of Biochemistry and Molecular Biology, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityDepartment of Biochemistry and Molecular Biology, Thomas Jefferson UniversityWeinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson UniversityAbstract Expanded intronic G4C2 repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapβ2 is detrimental to their survival, whereas increased Kapβ2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapβ2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapβ2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.https://doi.org/10.1038/s42003-024-06071-2 |
| spellingShingle | M. E. Cicardi V. Kankate S. Sriramoji K. Krishnamurthy S. S. Markandaiah B. M. Verdone A. Girdhar A. Nelson L. B. Rivas A. Boehringer A. R. Haeusler P. Pasinelli L. Guo D. Trotti The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD Communications Biology |
| title | The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD |
| title_full | The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD |
| title_fullStr | The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD |
| title_full_unstemmed | The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD |
| title_short | The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD |
| title_sort | nuclear import receptor kapβ2 modifies neurotoxicity mediated by poly gr in c9orf72 linked als ftd |
| url | https://doi.org/10.1038/s42003-024-06071-2 |
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