Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects
Abstract Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-024-01742-x |
| _version_ | 1797272838621626368 |
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| author | Andrea Markovinovic Sandra M. Martín-Guerrero Gábor M. Mórotz Shaakir Salam Patricia Gomez-Suaga Sebastien Paillusson Jenny Greig Younbok Lee Jacqueline C. Mitchell Wendy Noble Christopher C.J. Miller |
| author_facet | Andrea Markovinovic Sandra M. Martín-Guerrero Gábor M. Mórotz Shaakir Salam Patricia Gomez-Suaga Sebastien Paillusson Jenny Greig Younbok Lee Jacqueline C. Mitchell Wendy Noble Christopher C.J. Miller |
| author_sort | Andrea Markovinovic |
| collection | DOAJ |
| description | Abstract Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiological functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of ER to the mitochondrial surface so as to facilitate inter-organelle communications. Several studies have now shown that disrupted ER-mitochondria signaling including breaking of the VAPB-PTPIP51 tethers are features of FTD/ALS and that for TDP43 and other familial genetic FTD/ALS insults, this involves activation of glycogen kinase-3β (GSK3β). Such findings have prompted suggestions that correcting damage to ER-mitochondria signaling and the VAPB-PTPIP51 interaction may be broadly therapeutic. Here we provide evidence to support this notion. We show that overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling corrects mutant TDP43 induced damage to inositol 1,4,5-trisphosphate (IP3) receptor delivery of Ca2+ to mitochondria which is a primary function of the VAPB-PTPIP51 tethers, and to synaptic function. Moreover, we show that ursodeoxycholic acid (UDCA), an FDA approved drug linked to FTD/ALS and other neurodegenerative diseases therapy and whose precise therapeutic target is unclear, corrects TDP43 linked damage to the VAPB-PTPIP51 interaction. We also show that this effect involves inhibition of TDP43 mediated activation of GSK3β. Thus, correcting damage to the VAPB-PTPIP51 tethers may have therapeutic value for FTD/ALS and other age-related neurodegenerative diseases. |
| first_indexed | 2024-03-07T14:36:04Z |
| format | Article |
| id | doaj.art-959726ed7de941829423f9bf27ab624c |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-07T14:36:04Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-959726ed7de941829423f9bf27ab624c2024-03-05T20:40:41ZengBMCActa Neuropathologica Communications2051-59602024-02-0112111710.1186/s40478-024-01742-xStimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defectsAndrea Markovinovic0Sandra M. Martín-Guerrero1Gábor M. Mórotz2Shaakir Salam3Patricia Gomez-Suaga4Sebastien Paillusson5Jenny Greig6Younbok Lee7Jacqueline C. Mitchell8Wendy Noble9Christopher C.J. Miller10Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonAbstract Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiological functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of ER to the mitochondrial surface so as to facilitate inter-organelle communications. Several studies have now shown that disrupted ER-mitochondria signaling including breaking of the VAPB-PTPIP51 tethers are features of FTD/ALS and that for TDP43 and other familial genetic FTD/ALS insults, this involves activation of glycogen kinase-3β (GSK3β). Such findings have prompted suggestions that correcting damage to ER-mitochondria signaling and the VAPB-PTPIP51 interaction may be broadly therapeutic. Here we provide evidence to support this notion. We show that overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling corrects mutant TDP43 induced damage to inositol 1,4,5-trisphosphate (IP3) receptor delivery of Ca2+ to mitochondria which is a primary function of the VAPB-PTPIP51 tethers, and to synaptic function. Moreover, we show that ursodeoxycholic acid (UDCA), an FDA approved drug linked to FTD/ALS and other neurodegenerative diseases therapy and whose precise therapeutic target is unclear, corrects TDP43 linked damage to the VAPB-PTPIP51 interaction. We also show that this effect involves inhibition of TDP43 mediated activation of GSK3β. Thus, correcting damage to the VAPB-PTPIP51 tethers may have therapeutic value for FTD/ALS and other age-related neurodegenerative diseases.https://doi.org/10.1186/s40478-024-01742-xNeurodegenerative diseasesFrontotemporal dementiaAmyotrophic lateral sclerosisTDP43Alzheimer’s diseaseParkinson’s disease |
| spellingShingle | Andrea Markovinovic Sandra M. Martín-Guerrero Gábor M. Mórotz Shaakir Salam Patricia Gomez-Suaga Sebastien Paillusson Jenny Greig Younbok Lee Jacqueline C. Mitchell Wendy Noble Christopher C.J. Miller Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects Acta Neuropathologica Communications Neurodegenerative diseases Frontotemporal dementia Amyotrophic lateral sclerosis TDP43 Alzheimer’s disease Parkinson’s disease |
| title | Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects |
| title_full | Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects |
| title_fullStr | Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects |
| title_full_unstemmed | Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects |
| title_short | Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects |
| title_sort | stimulating vapb ptpip51 er mitochondria tethering corrects ftd als mutant tdp43 linked ca2 and synaptic defects |
| topic | Neurodegenerative diseases Frontotemporal dementia Amyotrophic lateral sclerosis TDP43 Alzheimer’s disease Parkinson’s disease |
| url | https://doi.org/10.1186/s40478-024-01742-x |
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