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

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Blood Platelets*/metabolism ; DNA-Binding Proteins*/metabolism ; Neurodegenerative Diseases*/blood ; Neurodegenerative Diseases*/metabolism ; Biological Specimen Banks*; Humans ; Amyotrophic Lateral Sclerosis/blood ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Biomarkers/blood ; Cytosol/metabolism

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.
(© 2024. The Author(s).)

Erratum in: Sci Rep. 2024 Nov 7;14(1):27147. doi: 10.1038/s41598-024-77057-7. (PMID: 39511249)

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BB-2022-C5 Target ALS Foundation; Industry-Led Consortium Project Grant Target ALS Foundation

0 (TARDBP protein, human)
0 (DNA-Binding Proteins)
0 (Biomarkers)

Date Created: 20240918 Date Completed: 20240918 Latest Revision: 20241109

20241109

PMC11410945

10.1038/s41598-024-70822-8

39294194