دورية أكاديمية
Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy
| العنوان: | Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy |
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| المؤلفون: | Bilal Khalil, Deepak Chhangani, Melissa C. Wren, Courtney L. Smith, Jannifer H. Lee, Xingli Li, Christian Puttinger, Chih-Wei Tsai, Gael Fortin, Dmytro Morderer, Junli Gao, Feilin Liu, Chun Kim Lim, Jingjiao Chen, Ching-Chieh Chou, Cara L. Croft, Amanda M. Gleixner, Christopher J. Donnelly, Todd E. Golde, Leonard Petrucelli, Björn Oskarsson, Dennis W. Dickson, Ke Zhang, James Shorter, Shige H. Yoshimura, Sami J. Barmada, Diego E. Rincon-Limas, Wilfried Rossoll |
| المصدر: | Molecular Neurodegeneration, Vol 17, Iss 1, Pp 1-27 (2022) |
| بيانات النشر: | BMC, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Neurology. Diseases of the nervous system LCC:Geriatrics |
| مصطلحات موضوعية: | Amyotrophic lateral sclerosis, Frontotemporal dementia, TDP-43, Nucleocytoplasmic transport, Importin, Nuclear pore, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6 |
| الوصف: | Abstract Background Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-β1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology. Methods We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention of aggregation of recombinant TDP-43 fibrils in vitro. Fly models of TDP-43 proteinopathy were used to determine the effect of KPNB1 on their neurodegenerative phenotype in vivo. Results We discovered that several members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, we found that its activity depends on the prion-like C-terminal region of TDP-43, which mediates the co-aggregation with phenylalanine and glycine-rich nucleoporins (FG-Nups) such as Nup62. KPNB1 is recruited into these co-aggregates where it acts as a molecular chaperone that reverses aberrant phase transition of Nup62 and TDP-43. These findings are supported by the discovery that Nup62 and KPNB1 are also sequestered into pathological TDP-43 aggregates in ALS/FTD postmortem CNS tissue, and by the identification of the fly ortholog of KPNB1 as a strong protective modifier in Drosophila models of TDP-43 proteinopathy. Our results show that KPNB1 can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD. Conclusion Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by FG-Nups in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration. Graphical Abstract |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1750-1326 |
| العلاقة: | https://doaj.org/toc/1750-1326Test |
| DOI: | 10.1186/s13024-022-00585-1 |
| الوصول الحر: | https://doaj.org/article/bbd064334e3c44abbee70cb5d84f3100Test |
| رقم الانضمام: | edsdoj.bbd064334e3c44abbee70cb5d84f3100 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17501326 |
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| DOI: | 10.1186/s13024-022-00585-1 |