A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms

Topic: Brain proteins, microglia and lab models

TDP-43 pathology is a hallmark of fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43-encephalopathy (LATE). In affected patients, cytoplasmic TDP-43 aggregates are accompanied by disruption of its normal nuclear localization and function. Because TDP-43 is an RNA binding protein that controls transcript processing, including repression of cryptic exon splicing, its loss leads to dysregulation of gene expression. Despite its central significance in disease, the connection between TDP-43 aggregation and dysfunction remains poorly understood, and models to study the underlying mechanisms are limited. Here, we characterize a robust and quantitative cell-based reporter that captures both aggregation and the resulting loss of function. Using this human biosensor cell line, we show that aggregation initiated by prion-like seeding drives progressive depletion of nuclear TDP-43 and induces signature features of diminished TDP-43 activity, such as increased DNA damage and activation of cryptic exon splicing. We find that aggregate seeding also induces cryptic exon splicing in human neurons implying that this pathological link extends to disease-relevant models. The seeding model provides a platform for dissecting mechanisms that underlie TDP-43 pathology and for identifying factors that modulate the aggregation-to-dysfunction transition. Our data shows that aggregate seeding impacts TDP-43 autoregulation, initiating a toxic feed-forward mechanism that disrupts TDP-43 homeostasis. Furthermore, reducing ataxin-2 levels decreases aggregation and restores TDP-43 activity. Together, these findings reveal a molecularly guided strategy to directly impact TDP-43 activity by decreasing its misfolding and aggregation, highlighting approaches to prevent TDP-43 dysfunction and mitigate toxicity under pathological conditions.

Key findings

• Together, these findings reveal a molecularly guided strategy to directly impact TDP-43 activity by decreasing its misfolding and aggregation, highlighting approaches to prevent TDP-43 dysfunction and mitigate toxicity under pathological conditions.

Why it matters

Using a cell-based reporter, this study showed that seeding-driven TDP-43 aggregation causes progressive loss of nuclear TDP-43 and features of reduced TDP-43 activity, including DNA damage and cryptic exon splicing, with similar splicing seen in human neurons. The authors describe this as a platform for finding ways to reduce TDP-43 misfolding and aggregation and limit its toxicity.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1371/journal.pbio.3003662
• PubMed: 41875078
• 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{mamede2026-41875078,
  author  = {Mamede, Lohany Dias and Hu, Miwei and Vaquer-Alicea, Jaime III and Titus, Amanda R. and dos Passos, Patricia M. and Lantelme, Erica and French, Rachel L. and Kirschner, Paige A. and others},
  title   = {{A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms}},
  journal = {PLoS Biology},
  year    = {2026},
  doi     = {10.1371/journal.pbio.3003662},
  pmid    = {41875078},
  url     = {https://doi.org/10.1371/journal.pbio.3003662}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 21.

• Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report Brain : a journal of neurology · 2019-06-01 · usefulness score 67/100 · Prevention and risk
• The spectrum of disease in chronic traumatic encephalopathy Brain : a journal of neurology · 2012-12-02 · usefulness score 66/100 · Getting a diagnosis
• 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
• Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice Nature · 2017-04-12 · usefulness score 61/100 · Lewy body dementia
• TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions The American journal of pathology · 2007-07-01 · usefulness score 59/100 · Lewy body dementia
• Structure of pathological TDP-43 filaments from ALS with FTLD Nature · 2021-12-08 · usefulness score 58/100 · Lewy body dementia
• Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD) Acta neuropathologica · 2014-01-10 · usefulness score 57/100 · Caregiving
• 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

Related studies in Brain tissue and pathology

• Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction Science Translational Medicine · 2026-06-03 · usefulness score 51/100
• Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses Cells · 2025-05-08 · usefulness score 44/100
• Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases Nature reviews. Molecular cell biology · 2024-08-06 · usefulness score 60/100
• Vascular dysfunction in the pathogenesis of Alzheimer's disease--A review of endothelium-mediated mechanisms and ensuing vicious circles Neurobiology of disease · 2015-08-23 · usefulness score 46/100
• TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia Journal of neurology, neurosurgery, and psychiatry · 2008-10-01 · usefulness score 49/100
• The Association Between Quantitative Measures of Dementia and of Senile Change in the Cerebral Grey Matter of Elderly Subjects The British Journal of Psychiatry · 1968-07-01 · usefulness score 53/100

Also tagged “mice”

1,150 studies in the library carry the topic tag “mice”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

• TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy Journal of neuropathology and experimental neurology · 2010-09-01 · usefulness score 53/100 · Lewy body dementia
• Clemastine ameliorates cognitive deficits in an experimental rat model of chronic cerebral hypoperfusion Journal of Cerebral Blood Flow & Metabolism · 2025-11-03 · usefulness score 35/100 · Disease mechanisms
• Direct and indirect role of non-coding RNAs in company with amyloid and tau protein in promoting neuroinflammation in post-ischemic brain neurodegeneration Frontiers in Cellular Neuroscience · 2025-10-31 · usefulness score 36/100 · Inflammation and the immune system

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More on Brain tissue and pathology

• A review that covers this ground TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2015-04-01 · usefulness score 50/100
• Newest in this subject Inflammatory biomarker candidates in dementia with Lewy bodies: diagnostic classification, clinical associations, and survival Research Square · 2026-11-01 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject TMEM106B C-Terminal fragment aggregation exacerbates α-synuclein and TDP-43 proteinopathy phenotypes bioRxiv · 2026-10-30 · Preprint — not yet peer-reviewed · usefulness score 16/100

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