TDP-43-mediated alternative polyadenylation is associated with a reduction in VPS35 and VPS29 expression in frontotemporal dementia

Topic: Brain proteins, microglia and lab models

TAR DNA-binding protein 43 (TDP-43) dysfunction is a hallmark of several neurodegenerative diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease. Although cryptic exon inclusion is a well-characterized consequence of TDP-43 loss of function, emerging evidence reveals broader roles in RNA metabolism, notably in the regulation of alternative polyadenylation (APA) of disease-relevant transcripts. In the present study, we examined 3' untranslated region lengthening events in the brains of individuals with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), focusing on the functional impact of APA dysregulation. To investigate whether TDP-43-mediated APA events occur in the postmortem brain, we measured the 3' untranslated region length of the retromer component vacuolar protein sorting 35 (VPS35) and the ETS transcription factor (ELK1) in the frontal cortex of a large cohort of FTLD-TDP patients and of healthy controls, and evaluated if these APA events are associated with FTLD-TDP clinical characteristic, markers of TDP-43 pathology [e.g., hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA], or the expression of VPS35 and VPS29 proteins, the latter being essential to the retromer complex. We identified robust 3' untranslated region lengthening of VPS35 and ELK1 in FTLD-TDP, which strongly associated with markers of TDP-43 pathology, and ELK1 APA also associated with an earlier age of disease onset. Functionally, VPS35 APA was associated with reduced VPS35 and VPS29 protein expression, and lower VPS35 levels were associated with increased hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA. Together, these data implicate APA dysregulation as a critical downstream consequence of TDP-43 dysfunction and suggest that TDP-43 loss may contribute to retromer impairment through APA-mediated repression of retromer subunits.

Key findings

• To investigate whether TDP-43-mediated APA events occur in the postmortem brain, we measured the 3' untranslated region length of the retromer component vacuolar protein sorting 35 (VPS35) and the ETS transcription factor (ELK1) in the frontal cortex of a large cohort of FTLD-TDP patients and of healthy controls, and evaluated if these APA events are associated with FTLD-TDP clinical characteristic, markers of TDP-43 pathology [e.g., hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA], or the expression of VPS35 and VPS29 proteins, the latter being essential to the retromer complex.
• We identified robust 3' untranslated region lengthening of VPS35 and ELK1 in FTLD-TDP, which strongly associated with markers of TDP-43 pathology, and ELK1 APA also associated with an earlier age of disease onset.
• Functionally, VPS35 APA was associated with reduced VPS35 and VPS29 protein expression, and lower VPS35 levels were associated with increased hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA.
• Together, these data implicate APA dysregulation as a critical downstream consequence of TDP-43 dysfunction and suggest that TDP-43 loss may contribute to retromer impairment through APA-mediated repression of retromer subunits.

Why it matters

In post-mortem frontal cortex from people with frontotemporal lobar degeneration with TDP-43 pathology, this study found lengthening of the 3' untranslated region of VPS35 and ELK1, associated with markers of TDP-43 pathology and reduced VPS35 and VPS29 protein expression. This describes a molecular mechanism and does not test any treatment, cure or prevention.

Study details

• Evidence strengthModerate

Read the original

• DOI: 10.1371/journal.pbio.3003573
• PubMed: 41490046
• Original source →
• Free full text: PLoS Biology →

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

@article{bharathi2026-41490046,
  author  = {Bharathi, Vidhya and Zeng, Yi and Armour, Ellen M. and Yue, Mei and Citrano, Kathryn and Lovchykova, Anastasiia and Reeves, Madison M. and Rawlinson, Bailey D. and others},
  title   = {{TDP-43-mediated alternative polyadenylation is associated with a reduction in VPS35 and VPS29 expression in frontotemporal dementia}},
  journal = {PLoS Biology},
  year    = {2026},
  doi     = {10.1371/journal.pbio.3003573},
  pmid    = {41490046},
  url     = {https://doi.org/10.1371/journal.pbio.3003573}
}

Studies this one cites

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• TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration Nature neuroscience · 2019-01-14 · usefulness score 62/100 · Lewy body dementia
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · Lewy body dementia
• Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits Science (New York, N.Y.) · 2015-05-14 · usefulness score 57/100 · Lewy body dementia
• TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD Science (New York, N.Y.) · 2015-08-01 · usefulness score 57/100 · Lewy body dementia
• Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia The Journal of clinical investigation · 2020-11-01 · usefulness score 57/100 · Brain tissue and pathology
• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration Human molecular genetics · 2010-04-15 · usefulness score 56/100 · Lewy body dementia
• TDP-43 loss induces cryptic polyadenylation in ALS/FTD Nature Neuroscience · 2025-10-21 · usefulness score 56/100 · Brain tissue and pathology
• TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes Nature Neuroscience · 2025-10-21 · usefulness score 55/100 · Brain tissue and pathology
• Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease Neuron · 2013-09-01 · usefulness score 54/100 · TREM2 and immune genetics

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• Accumulation of dipeptide repeat proteins predates that of TDP ‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene Neuropathology and Applied Neurobiology · 2015-04-30 · usefulness score 36/100

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