Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols
Abstract The TAR DNA Binding Protein 43 (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization a...
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Nature Portfolio
2024-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-70822-8 |
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| author | Ruth Luthi-Carter Sara Cappelli Morgan Le Roux-Bourdieu Noemie Tentillier James P. Quinn Tiziana Petrozziello Lathika Gopalakrishnan Purva Sethi Himanshi Choudhary Giorgia Bartolini Elias Gebara Cristiana Stuani Laure Font Jiyan An Vanessa Ortega Jessica Sage Edina Kosa Bianca A. Trombetta Roberto Simeone Tamara Seredenina Tariq Afroz James D. Berry Steven E. Arnold Becky C. Carlyle Oskar Adolfsson Ghazaleh Sadri-Vakili Emanuele Buratti Robert Bowser Abdulbaki Agbas |
| author_facet | Ruth Luthi-Carter Sara Cappelli Morgan Le Roux-Bourdieu Noemie Tentillier James P. Quinn Tiziana Petrozziello Lathika Gopalakrishnan Purva Sethi Himanshi Choudhary Giorgia Bartolini Elias Gebara Cristiana Stuani Laure Font Jiyan An Vanessa Ortega Jessica Sage Edina Kosa Bianca A. Trombetta Roberto Simeone Tamara Seredenina Tariq Afroz James D. Berry Steven E. Arnold Becky C. Carlyle Oskar Adolfsson Ghazaleh Sadri-Vakili Emanuele Buratti Robert Bowser Abdulbaki Agbas |
| author_sort | Ruth Luthi-Carter |
| collection | DOAJ |
| description | Abstract The TAR DNA Binding Protein 43 (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization and possible functions in the cytosol of platelets. Novel TDP-43 immunoassays were developed on three different technical platforms and qualified for specificity, signal-to-noise ratio, detection range, variation, spike recovery and dilution linearity in human plasma samples. Surprisingly, implementation of these assays demonstrated that biobank-archived plasma samples yielded considerable heterogeneity in TDP-43 levels. Importantly, subsequent investigation attributed these differences to variable platelet recovery. Fractionations of fresh blood revealed that ≥ 95% of the TDP-43 in platelet-containing plasma was compartmentalized within the platelet cytosol. We reasoned that this highly concentrated source of TDP-43 comprised an interesting substrate for biochemical analyses. Additional characterization of platelets revealed the presence of the disease-associated phosphoserine 409/410 TDP-43 proteoform and many neuron- and astrocyte-expressed TDP-43 mRNA targets. Considering these striking similarities, we propose that TDP-43 may serve analogous functional roles in platelets and synapses, and that the study of platelet TDP-43 might provide a window into disease-related TDP-43 dyshomeostasis in the central nervous system. |
| format | Article |
| id | doaj-art-a0db3bccec97456caa51182a2870d211 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-a0db3bccec97456caa51182a2870d2112024-11-10T12:21:45ZengNature PortfolioScientific Reports2045-23222024-09-0114111910.1038/s41598-024-70822-8Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocolsRuth Luthi-Carter0Sara Cappelli1Morgan Le Roux-Bourdieu2Noemie Tentillier3James P. Quinn4Tiziana Petrozziello5Lathika Gopalakrishnan6Purva Sethi7Himanshi Choudhary8Giorgia Bartolini9Elias Gebara10Cristiana Stuani11Laure Font12Jiyan An13Vanessa Ortega14Jessica Sage15Edina Kosa16Bianca A. Trombetta17Roberto Simeone18Tamara Seredenina19Tariq Afroz20James D. Berry21Steven E. Arnold22Becky C. Carlyle23Oskar Adolfsson24Ghazaleh Sadri-Vakili25Emanuele Buratti26Robert Bowser27Abdulbaki Agbas28AC Immune, SA (ACIU)International Centre for Genetic Engineering and BiotechnologyAC Immune, SA (ACIU)AC Immune, SA (ACIU)Massachusetts General Hospital Department of NeurologySean M. Healey and AMG Center for ALS at MassGeneral, Massachusetts General HospitalDepartment of Translational Neuroscience, Barrow Neurological InstituteKansas City UniversityInternational Centre for Genetic Engineering and BiotechnologyAC Immune, SA (ACIU)AC Immune, SA (ACIU)International Centre for Genetic Engineering and BiotechnologyAC Immune, SA (ACIU)Department of Translational Neuroscience, Barrow Neurological InstituteDepartment of Translational Neuroscience, Barrow Neurological InstituteKansas City UniversityKansas City UniversityMassachusetts General Hospital Department of NeurologyDipartimento di Medicina Trasfusionale Giuliano-Isontina, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI)AC Immune, SA (ACIU)AC Immune, SA (ACIU)Massachusetts General Hospital Department of NeurologyMassachusetts General Hospital Department of NeurologyMassachusetts General Hospital Department of NeurologyAC Immune, SA (ACIU)Massachusetts General Hospital Department of NeurologyInternational Centre for Genetic Engineering and BiotechnologyDepartment of Translational Neuroscience, Barrow Neurological InstituteKansas City UniversityAbstract The TAR DNA Binding Protein 43 (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization and possible functions in the cytosol of platelets. Novel TDP-43 immunoassays were developed on three different technical platforms and qualified for specificity, signal-to-noise ratio, detection range, variation, spike recovery and dilution linearity in human plasma samples. Surprisingly, implementation of these assays demonstrated that biobank-archived plasma samples yielded considerable heterogeneity in TDP-43 levels. Importantly, subsequent investigation attributed these differences to variable platelet recovery. Fractionations of fresh blood revealed that ≥ 95% of the TDP-43 in platelet-containing plasma was compartmentalized within the platelet cytosol. We reasoned that this highly concentrated source of TDP-43 comprised an interesting substrate for biochemical analyses. Additional characterization of platelets revealed the presence of the disease-associated phosphoserine 409/410 TDP-43 proteoform and many neuron- and astrocyte-expressed TDP-43 mRNA targets. Considering these striking similarities, we propose that TDP-43 may serve analogous functional roles in platelets and synapses, and that the study of platelet TDP-43 might provide a window into disease-related TDP-43 dyshomeostasis in the central nervous system.https://doi.org/10.1038/s41598-024-70822-8 |
| spellingShingle | Ruth Luthi-Carter Sara Cappelli Morgan Le Roux-Bourdieu Noemie Tentillier James P. Quinn Tiziana Petrozziello Lathika Gopalakrishnan Purva Sethi Himanshi Choudhary Giorgia Bartolini Elias Gebara Cristiana Stuani Laure Font Jiyan An Vanessa Ortega Jessica Sage Edina Kosa Bianca A. Trombetta Roberto Simeone Tamara Seredenina Tariq Afroz James D. Berry Steven E. Arnold Becky C. Carlyle Oskar Adolfsson Ghazaleh Sadri-Vakili Emanuele Buratti Robert Bowser Abdulbaki Agbas Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols Scientific Reports |
| title | Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols |
| title_full | Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols |
| title_fullStr | Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols |
| title_full_unstemmed | Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols |
| title_short | Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols |
| title_sort | location and function of tdp 43 in platelets alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols |
| url | https://doi.org/10.1038/s41598-024-70822-8 |
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