Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice

Topic: Brain proteins, microglia and lab models

Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.

@article{xu2010-20702714,
  author  = {Xu, Y. F. and Gendron, T. F. and Zhang, Y. J. and Lin, W. L. and D'Alton, S. and Sheng, H. and Casey, M. C. and Tong, J. and others},
  title   = {{Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice}},
  journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
  year    = {2010},
  doi     = {10.1523/jneurosci.1630-10.2010},
  pmid    = {20702714},
  url     = {https://doi.org/10.1523/jneurosci.1630-10.2010}
}

Key findings

• Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations.
• While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions.

Why it matters

In transgenic mice, expressing wild-type human TDP-43 caused TDP-43 phosphorylation, mitochondrial aggregation, motor deficits and early mortality. This is an animal model of disease mechanisms, not evidence that any treatment helps patients.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1523/jneurosci.1630-10.2010
• PubMed: 20702714
• Original source →
• Free full text: Journal of Neuroscience →

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Studies this one cites

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

• Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis PLoS genetics · 2008-09-19 · usefulness score 65/100 · Lewy body dementia
• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• 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
• 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
• Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity Proceedings of the National Academy of Sciences of the United States of America · 2009-04-21 · usefulness score 55/100 · Lewy body dementia
• Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Annals of neurology · 2008-07-01 · usefulness score 54/100 · Lewy body dementia
• Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43 The Journal of neuroscience : the official journal of the Society for Neuroscience · 2007-09-01 · usefulness score 53/100 · Lewy body dementia
• TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration Proceedings of the National Academy of Sciences of the United States of America · 2009-10-15 · usefulness score 52/100 · Lewy body dementia
• TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration Proceedings of the National Academy of Sciences of the United States of America · 2010-02-03 · usefulness score 52/100 · Lewy body dementia

Later studies that cite this one

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• The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity Nature medicine · 2016-06-27 · usefulness score 58/100 · Lewy body dementia
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• Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology Acta neuropathologica · 2018-12-03 · usefulness score 55/100 · Disparities
• ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43 Nature communications · 2014-06-03 · usefulness score 55/100 · Brain tissue and pathology
• 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
• Frontotemporal Dementia, Where Do We Stand? A Narrative Review International journal of molecular sciences · 2023-07-21 · usefulness score 52/100 · Digital health tools
• Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice The Journal of clinical investigation · 2011-01-04 · usefulness score 52/100 · Lewy body dementia

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