Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances

Topic: Brain proteins, microglia and lab models

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding protein involved in various cellular processes, including RNA splicing, transcription regulation, and RNA stability. Mislocalization and aggregation of TDP-43 in the cytoplasm are key features of the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). This review provides a comprehensive retrospective and prospective analysis of TDP-43 research, highlighting structural insights, significant milestones, and the evolving understanding of its physiological and pathological functions. We delineate five major stages in TDP-43 research, from its initial discovery as a pathological hallmark in neurodegeneration to the recent advances in understanding its liquid-liquid phase separation (LLPS) behavior and interactions with cellular processes. Furthermore, we assess therapeutic strategies targeting TDP-43 pathology, categorizing approaches into direct and indirect interventions, alongside modulating aberrant TDP-43 LLPS. We propose that future research will focus on three critical areas: targeting TDP-43 structural polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation of TDP-43, and advancing nano-therapy. More importantly, we emphasize the importance of understanding TDP-43's functional repertoire at the mesoscale, which bridges its molecular functions with broader cellular processes. This review offers a foundational framework for advancing TDP-43 research and therapeutic development.

@article{dang2025-40032118,
  author  = {Dang, Mei and Wu, Longjiang and Zhang, Xiaoying},
  title   = {{Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances}},
  journal = {International Journal of Biological Macromolecules},
  year    = {2025},
  doi     = {10.1016/j.ijbiomac.2025.141677},
  pmid    = {40032118},
  url     = {https://doi.org/10.1016/j.ijbiomac.2025.141677}
}

Key findings

• This review provides a comprehensive retrospective and prospective analysis of TDP-43 research, highlighting structural insights, significant milestones, and the evolving understanding of its physiological and pathological functions.

Why it matters

This review covers the history and structural understanding of TDP-43 and assesses therapeutic strategies targeting TDP-43 pathology, including direct and indirect approaches and modulating its phase separation. It proposes future research directions but reports no treatment that has been shown to cure or prevent disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.ijbiomac.2025.141677
• PubMed: 40032118
• Original source →
• Free full text: International Journal of Biological Macromolecules →

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

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 26.

• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• 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
• TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis The Lancet. Neurology · 2008-04-07 · usefulness score 61/100 · Lewy body dementia
• TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD Nature neuroscience · 2018-01-08 · usefulness score 61/100 · Lewy body dementia
• Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies Science (New York, N.Y.) · 2023-03-16 · usefulness score 60/100 · Brain tissue and pathology
• The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity Nature medicine · 2016-06-27 · usefulness score 58/100 · Lewy body dementia
• Structure of pathological TDP-43 filaments from ALS with FTLD Nature · 2021-12-08 · usefulness score 58/100 · Lewy body dementia
• 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
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death Neuron · 2019-03-07 · usefulness score 56/100 · Lewy body dementia

Later studies that cite this one

1 study in the alzhub library lists this one in its references.

• Looking into Abnormal Co-Expressions of Tau and TDP-43 in the Realm of Mixed Dementia Types: A Double-Punch Scenario Brain Sciences · 2025-07-03 · usefulness score 40/100 · Brain tissue and pathology

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• 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
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• Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain Nature Communications · 2025-11-26 · usefulness score 52/100
• Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology Neurotherapeutics · 2026-01-01 · usefulness score 38/100
• TDP ‐43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models FEBS Journal · 2025-09-02 · usefulness score 43/100
• Psychosocial burdens in early- versus late-onset dementia: analysis of discrimination, stress, and loneliness in the All of Us Research Program Innovation in Aging · 2025-01-01 · usefulness score 40/100

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• A review that covers this ground Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological inclusions in ALS? Frontiers in cellular neuroscience · 2015-10-23 · usefulness score 45/100
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