| ALS and frontotemporal dementia | Rare Neurological Diseases  

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD

This study provides further insights in the consequences of mislocalization of the protein TDP-43 from the nucleus to the cytoplasm which is a hallmark of almost all forms of ALS. The authors identified proteins generated from so called cryptic exon inclusions arising from TDP-43 misfunction. These newly identified proteins may be used as disease biomarkers and for novel treatment strategies.

Cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) are the neuropathological hallmark of both sporadic and most cases of familial amyotrophic lateral sclerosis (ALS) and can also be detected in a proportion of patients with frontotemporal dementia (FTD) and Alzheimer’s disease (AD). In recent years, it has been demonstrated that TDP-43 acts as inhibitor of mis-splicing and thereby represses erroneous inclusion of intronic sequences (called cryptic exons) during RNA splicing. Nuclear depletion of TDP-43 in cortical and spinal neurons results in cryptic exon inclusion and thereby degradation of affected transcripts and decreased RNA and protein expression of a large number of genes including stathmin-2 (STMN2) and UNC13A (1-3).

In the present study, published as preprint in bioRxiv, Seddighi et al. (1) performed proteomic and transcriptomic analyses in induced pluripotent stem cell (iPSC)-based cellular models to show that these cryptic exons also result in generation of de novo peptide sequences. They demonstrated that inclusion of cryptic peptide sequences in proteins altered interactions with other proteins and protein function. Moreover, they could detect these peptides in brain tissue and cerebrospinal fluid of ALS patients.

This not only highlights the possibility to use these de novo proteins as sensitive disease markers in ALS and FTD but also to identify novel therapeutic targets relevant for both familial and sporadic ALS.

Key points:

  • Nuclear loss of DTP-43 function results in mis-splicing and cryptic exon inclusion, so far mainly associated with subsequent loss of gene and protein expression
  • The authors have now identified proteins generated de novo from these cryptic exons
  • These de novo proteins may provide insights in disease pathophysiology, serve as valuable disease markers, and possibly help to find novel therapeutic targets for treatment of sporadic and familial ALS
  • Loss of nuclear function of TDP-43 leads to RNA mis-splicing and inclusion of cryptic exons which result in generation of de novo proteins with potential for biomarker and therapy development.

References:

  1. Seddighi S, Qi YA, Brown AL, Wilkins OG, Bereda C, Belair C, Zhang Y, Prudencio M, Keuss MJ, Khandeshi A, Pickles S, Hill SE, Hawrot J, Ramos DM, Yuan H, Roberts J, Kelmer Sacramento E, Shah SI, Nalls MA, Colon-Mercado J, Reyes JF, Ryan VH, Nelson MP, Cook C, Li Z, Screven L, Kwan JY, Shantaraman A, Ping L, Koike Y, Oskarsson B, Staff N, Duong DM, Ahmed A, Secrier M, Ule J, Jacobson S, Rohrer J, Malaspina A, Glass JD, Ori A, Seyfried NT, Maragkakis M, Petrucelli L, Fratta P, Ward ME (2023). Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD. bioRxiv 2023.01.23.525149. doi: 10.1101/2023.01.23.525149. Preprint.
  2. Akiyama T, Koike Y, Petrucelli L, Gitler AD (2022). Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers. Clin Transl Med 12:e818. doi: 10.1002/ctm2.818.
  3. Klim JR, Williams LA, Limone F, Guerra San Juan I, Davis-Dusenbery BN, Mordes DA, Burberry A, Steinbaugh MJ, Gamage KK, Kirchner R, Moccia R, Cassel SH, Chen K, Wainger BJ, Woolf CJ, Eggan K (2019). ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat. Neurosci. 22, 167–179.

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