Academic Journal
The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD
| العنوان: | The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD |
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| المؤلفون: | Cicardi, M. E., Kankate, V., Sriramoji, S., Krishnamurthy, K., Markandaiah, S. S., Verdone, B. M., Girdhar, A., Nelson, A., Rivas, L. B., Boehringer, A., Haeusler, A. R., Pasinelli, P., Guo, L., Trotti, D. |
| المساهمون: | U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke, U.S. Department of Health & Human Services | NIH | National Institute on Aging, U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences |
| المصدر: | Communications Biology ; volume 7, issue 1 ; ISSN 2399-3642 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2024 |
| الوصف: | Expanded intronic G 4 C 2 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s42003-024-06071-2 |
| الاتاحة: | http://dx.doi.org/10.1038/s42003-024-06071-2 https://www.nature.com/articles/s42003-024-06071-2.pdf https://www.nature.com/articles/s42003-024-06071-2 |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.D5602F16 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s42003-024-06071-2 |
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