Human TDP-43 overexpression in zebrafish motor neurons triggers MND-like phenotypes through gain-of-function mechanism

Topic: Brain proteins, microglia and lab models

Dysregulation of the TAR DNA-binding protein 43 (TDP-43), including intraneuronal cytoplasmic mislocalisation and aggregation is a feature of multiple neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD), limbic-predominant age-related TDP-43 encephalopathy (LATE) and alzheimer’s disease (AD). Unravelling the causes and functional consequences of TDP-43 dysregulation is paramount to understanding disease mechanisms as well as identifying effective therapeutic targets. Here we present a comprehensive in vivo characterisation of three stable transgenic zebrafish models that express human TDP-43 variants in motor neurons. We demonstrate that overexpression of predominantly nuclear wildtype TDP-43, cytoplasm-targeted TDP-43, and an ALS-linked variant (G294V) each induce toxic gain-of-function effects, leading to impaired motor function, motor neuron loss, and muscle atrophy. Importantly, these models reveal distinct phenotypes, with the ALS-linked mutant exhibiting axonal transport deficits and neuromuscular junction disruption, while cytoplasmic mislocalised TDP-43 heightened susceptibility to oxidative stress. Two FDA-approved drugs used to treat ALS, edaravone and riluzole, were examined in these models and revealed that edaravone, but not riluzole, was effective in rescuing motor deficits associated with cytoplasmic TDP-43 expression and, to a lesser extent, ALS-linked mutant TDP-43. Collectively, these findings reveal distinct pathological consequences of TDP-43 dysregulation, providing neuron-centric mechanistic insights, and establish the humanised TDP-43 zebrafish as an efficient system for preclinical therapeutic testing.

Key findings

• Two FDA-approved drugs used to treat ALS, edaravone and riluzole, were examined in these models and revealed that edaravone, but not riluzole, was effective in rescuing motor deficits associated with cytoplasmic TDP-43 expression and, to a lesser extent, ALS-linked mutant TDP-43.
• Collectively, these findings reveal distinct pathological consequences of TDP-43 dysregulation, providing neuron-centric mechanistic insights, and establish the humanised TDP-43 zebrafish as an efficient system for preclinical therapeutic testing.

Why it matters

Zebrafish engineered to produce human TDP-43 in motor neurons developed motor problems, motor neuron loss and muscle wasting, and the ALS drug edaravone but not riluzole improved motor deficits in some of these models. This is early animal work that may inform drug testing, but it does not yet show any treatment for people.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1186/s40478-025-02159-w
• PubMed: 41331940
• Original source →
• Free full text: Acta Neuropathologica Communications →

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

@article{hogan2025-41331940,
  author  = {Hogan, Alison L. and Kane, Madison A. and Chiu, Patrick Ka‐Chun and Richter, G. Stefan and Maurel, Cindy and Wu, Sharlynn and Scherer, Natalie M. and Don, Emily K. and others},
  title   = {{Human TDP-43 overexpression in zebrafish motor neurons triggers MND-like phenotypes through gain-of-function mechanism}},
  journal = {Acta Neuropathologica Communications},
  year    = {2025},
  doi     = {10.1186/s40478-025-02159-w},
  pmid    = {41331940},
  url     = {https://doi.org/10.1186/s40478-025-02159-w}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 20.

• 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
• TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations Annals of neurology · 2007-05-01 · usefulness score 63/100 · Brain tissue and pathology
• 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
• Animal models of neurodegenerative diseases Nature neuroscience · 2018-09-24 · 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
• TDP-43 Pathology in Alzheimer's Disease Molecular neurodegeneration · 2021-12-20 · usefulness score 56/100 · Lewy body dementia
• Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations Neuron · 2014-02-01 · usefulness score 55/100 · Lewy body dementia
• Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010-01-01 · usefulness score 54/100 · Lewy body dementia
• TDP-43 proteinopathies: a new wave of neurodegenerative diseases Journal of neurology, neurosurgery, and psychiatry · 2020-11-11 · usefulness score 54/100 · Lewy body dementia
• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100 · Lewy body dementia

Related studies in Brain tissue and pathology

• Human TDP-43 expression worsens FTD-related phenotypes in progranulin-insufficient mice Neurobiology of Disease · 2026-06-09 · usefulness score 36/100
• Gain-of-function ANXA11 mutation cause late-onset ALS with aberrant protein aggregation, neuroinflammation and autophagy impairment Acta Neuropathologica Communications · 2025-01-04 · usefulness score 43/100
• 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
• 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
• TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD Nature Neuroscience · 2025-10-31 · usefulness score 52/100
• Neurotoxic effects of TDP-43 overexpression in C. elegans Human molecular genetics · 2010-06-08 · usefulness score 47/100

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