A fluid biomarker reveals loss of TDP-43 splicing repression in pre-symptomatic ALS.
Katherine E IrwinPei JasinKerstin E BraunsteinIrika R SinhaKyra D BowdenAbhay MoghekarEsther S OhDenitza RaitchevaDan BartlettJames D BerryBryan J TraynorJonathan P LingPhilip C WongPublished in: bioRxiv : the preprint server for biology (2023)
Loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well-documented in postmortem tissues of amyotrophic lateral sclerosis (ALS), yet whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects functional loss of TDP-43, and thus detection of cryptic exon-encoded peptides in cerebrospinal fluid (CSF) could reveal the earliest stages of TDP-43 dysregulation in patients. Here, we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2 ) to show that loss of TDP-43 splicing repression occurs in C9ORF72 -associated ALS, including pre-symptomatic mutation carriers. In contrast to neurofilament light and heavy chain proteins, cryptic HDGFL2 accumulates in CSF at higher levels during early stages of disease. Our findings indicate that loss of TDP-43 splicing repression occurs early in disease progression, even pre-symptomatically, and that detection of HDGFL2’s cryptic neoepitope may serve as a prognostic test for ALS which should facilitate patient recruitment and measurement of target engagement in clinical trials.
Keyphrases
- amyotrophic lateral sclerosis
- cerebrospinal fluid
- monoclonal antibody
- early stage
- clinical trial
- binding protein
- gene expression
- squamous cell carcinoma
- magnetic resonance
- randomized controlled trial
- computed tomography
- social media
- chronic kidney disease
- radiation therapy
- single molecule
- neoadjuvant chemotherapy
- sentinel lymph node
- heat shock protein
- patient reported
- contrast enhanced