Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols

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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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2024-09-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-024-70822-8
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Summary: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.
ISSN:2045-2322

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