A novel fluid biomarker for TDP‐43 loss of function

Background TDP‐43 nuclear clearance and cytoplasmic aggregation occur in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis‐frontotemporal dementia (ALS‐FTD), Alzheimer’s disease (AD), and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). Nuclear clearance of TDP...

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Bibliographic Details
Published in:Alzheimer's & dementia 2023-12, Vol.19 (S24), p.n/a
Main Authors: Irwin, Katherine E, Jasin, Pei, Braunstein, Kerstin E, Sinha, Irika, Bowden, Kyra D, Moghekar, Abhay, Oh, Esther S, Raitcheva, Denitza, Bartlett, Dan, Berry, James D, Traynor, Bryan J, Ling, Jonathan P, Wong, Philip C
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Language:English
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Summary:Background TDP‐43 nuclear clearance and cytoplasmic aggregation occur in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis‐frontotemporal dementia (ALS‐FTD), Alzheimer’s disease (AD), and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). Nuclear clearance of TDP‐43 leads to its failure to repress splicing of nonconserved cryptic exons. This loss of TDP‐43 splicing repression is well‐documented in postmortem tissues, but there is currently no method of detecting TDP‐43 dysfunction in living patients. As some cryptic exons are spliced in‐frame and translated into proteins carrying novel epitopes, we hypothesize that these “cryptic peptides” may be found in patient CSF as biomarkers of TDP‐43 dysfunction. Method We generated novel monoclonal antibodies against several TDP‐43 cryptic exon targets and then developed a sandwich ELISA using the Meso Scale Discovery (MSD) platform, which we validated in cells deficient in TDP‐43 for the cryptic exon target in HDGFL2. We then screened CSF samples of C9ORF72‐mutation carriers with or at risk of ALS‐FTD and control individuals for the presence of this cryptic peptide. Result The MSD signal for cryptic HDGFL2 was elevated in CSF of C9ORF72‐mutation carriers with ALS (n = 5, mean = 1601) compared to those of controls (n = 5, mean = ‐64.10; p
ISSN:1552-5260
1552-5279
DOI:10.1002/alz.082829