Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD
Abstract Background Regulation of messenger RNA (mRNA) transport and translation in neurons is essential for dendritic plasticity and learning/memory development. The trafficking of mRNAs along the hippocampal neuron dendrites remains translationally silent until they are selectively transported int...
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BMC
2025-01-01
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| Series: | Cellular & Molecular Biology Letters |
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| Online Access: | https://doi.org/10.1186/s11658-024-00684-5 |
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| author | Pritha Majumder Biswanath Chatterjee Khadiza Akter Asmar Ahsan Su Jie Tan Chi-Chen Huang Jen-Fei Chu Che-Kun James Shen |
| author_facet | Pritha Majumder Biswanath Chatterjee Khadiza Akter Asmar Ahsan Su Jie Tan Chi-Chen Huang Jen-Fei Chu Che-Kun James Shen |
| author_sort | Pritha Majumder |
| collection | DOAJ |
| description | Abstract Background Regulation of messenger RNA (mRNA) transport and translation in neurons is essential for dendritic plasticity and learning/memory development. The trafficking of mRNAs along the hippocampal neuron dendrites remains translationally silent until they are selectively transported into the spines upon glutamate-induced receptor activation. However, the molecular mechanism(s) behind the spine entry of dendritic mRNAs under metabotropic glutamate receptor (mGluR)-mediated neuroactivation and long-term depression (LTD) as well as the fate of these mRNAs inside the spines are still elusive. Method Different molecular and imaging techniques, e.g., immunoprecipitation (IP), RNA-IP, Immunofluorescence (IF)/fluorescence in situ hybridization (FISH), live cell imaging, live cell tracking of RNA using beacon, and mouse model study are used to elucidate a novel mechanism regulating dendritic spine transport of mRNAs in mammalian neurons. Results We demonstrate here that brief mGluR1 activation-mediated dephosphorylation of pFMRP (S499) results in the dissociation of FMRP from TDP-43 and handover of TDP-43/Rac1 mRNA complex from the dendritic transport track on microtubules to myosin V track on the spine actin filaments. Rac1 mRNA thus enters the spines for translational reactivation and increases the mature spine density. In contrast, during mGluR1-mediated neuronal LTD, FMRP (S499) remains phosphorylated and the TDP-43/Rac1 mRNA complex, being associated with kinesin 1-FMRP/cortactin/drebrin, enters the spines owing to Ca2+-dependent microtubule invasion into spines, but without translational reactivation. In a VPA-ASD mouse model, this regulation become anomalous. Conclusions This study, for the first time, highlights the importance of posttranslational modification of RBPs, such as the neurodevelopmental disease-related protein FMRP, as the molecular switch regulating the dendrite-to-spine transport of specific mRNAs under mGluR1-mediated neurotransmissions. The misregulation of this switch could contribute to the pathogenesis of FMRP-related neurodisorders including the autism spectrum disorder (ASD). It also could indicate a molecular connection between ASD and neurodegenerative disease-related protein TDP-43 and opens up a new perspective of research to elucidate TDP-43 proteinopathy among patients with ASD. |
| format | Article |
| id | doaj-art-0f22d991dd004a25b9093f347d033d93 |
| institution | Kabale University |
| issn | 1689-1392 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Cellular & Molecular Biology Letters |
| spelling | doaj-art-0f22d991dd004a25b9093f347d033d932025-01-19T12:32:23ZengBMCCellular & Molecular Biology Letters1689-13922025-01-0130113710.1186/s11658-024-00684-5Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASDPritha Majumder0Biswanath Chatterjee1Khadiza Akter2Asmar Ahsan3Su Jie Tan4Chi-Chen Huang5Jen-Fei Chu6Che-Kun James Shen7PhD Program in Medical Neuroscience, Taipei Medical UniversityPhD Program in Medical Neuroscience, Taipei Medical UniversityPhD Program in Medical Neuroscience, Taipei Medical UniversityPhD Program in Medical Neuroscience, Taipei Medical UniversityInstitute of Molecular Medicine, College of Medicine, National Chen Kung UniversityPhD Program in Medical Neuroscience, Taipei Medical UniversityPhD Program in Medical Neuroscience, Taipei Medical UniversityPhD Program in Medical Neuroscience, Taipei Medical UniversityAbstract Background Regulation of messenger RNA (mRNA) transport and translation in neurons is essential for dendritic plasticity and learning/memory development. The trafficking of mRNAs along the hippocampal neuron dendrites remains translationally silent until they are selectively transported into the spines upon glutamate-induced receptor activation. However, the molecular mechanism(s) behind the spine entry of dendritic mRNAs under metabotropic glutamate receptor (mGluR)-mediated neuroactivation and long-term depression (LTD) as well as the fate of these mRNAs inside the spines are still elusive. Method Different molecular and imaging techniques, e.g., immunoprecipitation (IP), RNA-IP, Immunofluorescence (IF)/fluorescence in situ hybridization (FISH), live cell imaging, live cell tracking of RNA using beacon, and mouse model study are used to elucidate a novel mechanism regulating dendritic spine transport of mRNAs in mammalian neurons. Results We demonstrate here that brief mGluR1 activation-mediated dephosphorylation of pFMRP (S499) results in the dissociation of FMRP from TDP-43 and handover of TDP-43/Rac1 mRNA complex from the dendritic transport track on microtubules to myosin V track on the spine actin filaments. Rac1 mRNA thus enters the spines for translational reactivation and increases the mature spine density. In contrast, during mGluR1-mediated neuronal LTD, FMRP (S499) remains phosphorylated and the TDP-43/Rac1 mRNA complex, being associated with kinesin 1-FMRP/cortactin/drebrin, enters the spines owing to Ca2+-dependent microtubule invasion into spines, but without translational reactivation. In a VPA-ASD mouse model, this regulation become anomalous. Conclusions This study, for the first time, highlights the importance of posttranslational modification of RBPs, such as the neurodevelopmental disease-related protein FMRP, as the molecular switch regulating the dendrite-to-spine transport of specific mRNAs under mGluR1-mediated neurotransmissions. The misregulation of this switch could contribute to the pathogenesis of FMRP-related neurodisorders including the autism spectrum disorder (ASD). It also could indicate a molecular connection between ASD and neurodegenerative disease-related protein TDP-43 and opens up a new perspective of research to elucidate TDP-43 proteinopathy among patients with ASD.https://doi.org/10.1186/s11658-024-00684-5TDP-43pFMRP (S499)mRNP granuleRNA binding protein (RBP)Posttranslational modificationKinase |
| spellingShingle | Pritha Majumder Biswanath Chatterjee Khadiza Akter Asmar Ahsan Su Jie Tan Chi-Chen Huang Jen-Fei Chu Che-Kun James Shen Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD Cellular & Molecular Biology Letters TDP-43 pFMRP (S499) mRNP granule RNA binding protein (RBP) Posttranslational modification Kinase |
| title | Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD |
| title_full | Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD |
| title_fullStr | Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD |
| title_full_unstemmed | Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD |
| title_short | Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD |
| title_sort | molecular switch of the dendrite to spine transport of tdp 43 fmrp bound neuronal mrnas and its impairment in asd |
| topic | TDP-43 pFMRP (S499) mRNP granule RNA binding protein (RBP) Posttranslational modification Kinase |
| url | https://doi.org/10.1186/s11658-024-00684-5 |
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