Science translational medicineJan 26, 2024

Incorrectly processed RNA produces new proteins in TDP-43-linked ALS and FTD

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 25, 2026

Abstract

In cerebrospinal fluid samples from patients with ALS or FTD, 18 de novo peptides across 13 genes were detected.

Functional loss of TDP-43 leads to the inclusion of cryptic exons in hundreds of RNA transcripts.
These cryptic exons can degrade affected transcripts, potentially disrupting cellular functions.
In TDP-43-depleted neurons, 65 peptides corresponding to 12 cryptic exons were identified through transcriptomic and proteomic analyses.
Cryptic exons present in TDP-43-depleted neurons were found to predict those expressed in postmortem brain tissue from patients with TDP-43 proteinopathy.
The translation of cryptic exons results in the production of new proteins that may alter their interactions and functions.

Simplified

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

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Competing interests

Competing interests: The participation of M.A.N., Z.L., and S.I.S. in this project was part of a competitive contract awarded to Data Tecnica International LLC by the NIH to support open science research. M.A.N. also currently serves as an advisor for Character Biosciences and Neuron23 Inc. N.P.S. consults for Emtherapro. B.O. serves as a consultant for Columbia University/Tsumura Inc., MediciNova, Biogen, UniQure, Amylyx, and Mitsubishi. L. Petrucelli consults for Expansion Therapeutics.

PubMed

Incorrectly processed RNA produces new proteins in TDP-43-linked ALS and FTD

Abstract

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Competing interests

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