TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia

Topic: Brain proteins, microglia and lab models

Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from an RNA-Seq (DaPars) tool to ALS/FTD transcriptome datasets and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional relevance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3' UTRs, corresponding with a change in the subcellular distribution of MARK3 and increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously understudied feature of TDP-43-driven disease pathology in ALS/FTD and highlight a potentially important mechanistic link between TDP-43 dysfunction and tau regulation.

@article{arnold2025-40454469,
  author  = {Arnold, Frederick J. and Cui, Ya and Michels, Sebastian and Colwin, Michael R. and Stockford, Cameron M. and Ye, Wenbin and Bharathi, Vidhya and Jansen‐West, Karen R. and others},
  title   = {{TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia}},
  journal = {Journal of Clinical Investigation},
  year    = {2025},
  doi     = {10.1172/jci182088},
  pmid    = {40454469},
  url     = {https://doi.org/10.1172/jci182088}
}

Key findings

• Our findings define changes in polyadenylation site selection as a previously understudied feature of TDP-43-driven disease pathology in ALS/FTD and highlight a potentially important mechanistic link between TDP-43 dysfunction and tau regulation.

Why it matters

This study defines changes in polyadenylation site selection as a previously understudied feature of TDP-43-driven disease pathology in ALS/FTD. It highlights a potentially important mechanistic link between TDP-43 dysfunction and tau regulation, based on cell models and postmortem neuronal nuclei.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1172/jci182088
• PubMed: 40454469
• Original source →
• Free full text: Journal of Clinical Investigation →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

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