| Autor: |
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 |
| Zdroj: |
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Dec2023 Supplement 24, Vol. 19, p1-2, 2p |
| Abstrakt: |
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<0.013), so we examined a larger cohort of C9ORF72‐mutation carriers. In symptomatic individuals (n = 27), cryptic peptide levels showed a correlation nearing significance with symptom duration (r = ‐0.368, p = 0.059), suggesting that levels of the cryptic peptide tend to be higher during the earlier symptomatic phase. We also found elevated cryptic peptide levels in CSF of several pre‐symptomatic individuals. To clarify cryptic peptide dynamics during disease progression, we began to assess longitudinal CSF samples and found that in 82.35% (14/17) of symptomatic individuals, levels of the cryptic peptide decreased with disease progression. Conclusion: Our findings indicate that loss of TDP‐43 splicing repression occurs early in disease progression in ALS‐FTD, even pre‐symptomatically, and that detection of HDGFL2's cryptic neoepitope may facilitate earlier diagnosis of TDP‐43‐related diseases. Further efforts linking the presence of cryptic HGDFL2 to TDP‐43 co‐pathology in AD may help expand biomarker development in AD. Additionally, evaluating dynamics of these biomarkers could provide a way of measuring target engagement for new therapeutics aimed at restoring TDP‐43 function. [ABSTRACT FROM AUTHOR] |
| Databáze: |
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