TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration

Topic: Brain proteins, microglia and lab models

Neuronal cytoplasmic and intranuclear aggregates of RNA-binding protein TDP-43 are a hallmark feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). ALS and FTLD show a considerable clinical and pathological overlap and occur as both familial and sporadic forms. Though missense mutations in TDP-43 cause rare forms of familial ALS, it is not yet known whether this is due to loss of TDP-43 function or gain of aberrant function. Moreover, the role of wild-type (WT) TDP-43, associated with the majority of familial and sporadic ALS/FTLD patients, is also currently unknown. Generating homozygous and hemizygous WT human TDP-43 transgenic mouse lines, we show here a dose-dependent degeneration of cortical and spinal motor neurons and development of spastic quadriplegia reminiscent of ALS. A dose-dependent degeneration of nonmotor cortical and subcortical neurons characteristic of FTLD was also observed. Neurons in the affected spinal cord and brain regions showed accumulation of TDP-43 nuclear and cytoplasmic aggregates that were both ubiquitinated and phosphorylated as observed in ALS/FTLD patients. Moreover, the characteristic approximately 25-kDa C-terminal fragments (CTFs) were also recovered from nuclear fractions and correlated with disease development and progression in WT TDP-43 mice. These findings suggest that approximately 25-kDa TDP-43 CTFs are noxious to neurons by a gain of aberrant nuclear function.

Key findings

• Moreover, the role of wild-type (WT) TDP-43, associated with the majority of familial and sporadic ALS/FTLD patients, is also currently unknown.
• These findings suggest that approximately 25-kDa TDP-43 CTFs are noxious to neurons by a gain of aberrant nuclear function.

Why it matters

In mice, making wild-type human TDP-43 caused motor neuron degeneration and paralysis along with TDP-43 aggregates like those in ALS and FTLD patients. This is animal work only, and it suggests that a toxic gain of function by TDP-43 fragments may harm neurons, but no treatment is tested here.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1073/pnas.0912417107
• PubMed: 20133711
• Original source →
• Free full text: PubMed Central →

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

@article{wils2010-20133711,
  author  = {Wils, H. and Kleinberger, G. and Janssens, J. and Pereson, S. and Joris, G. and Cuijt, I. and Smits, V. and Ceuterick-de Groote, C. and others},
  title   = {{TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration}},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year    = {2010},
  doi     = {10.1073/pnas.0912417107},
  pmid    = {20133711},
  url     = {https://doi.org/10.1073/pnas.0912417107}
}

Studies this one cites

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

• The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics Science · 2002-07-19 · usefulness score 65/100 · Disease mechanisms
• 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
• TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration Annals of neurology · 2009-04-01 · usefulness score 54/100 · Brain tissue and pathology
• Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation The Journal of biological chemistry · 2008-02-27 · 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
• Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies The Journal of biological chemistry · 2009-01-21 · usefulness score 51/100 · Lewy body dementia
• Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis The American journal of pathology · 2008-06-05 · usefulness score 50/100 · Brain tissue and pathology
• Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40 Human mutation · 2006-07-01 · usefulness score 47/100 · Risk genes beyond APOE

Later studies that cite this one

27 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• 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
• 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
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia The Lancet. Neurology · 2010-10-01 · usefulness score 57/100 · Lewy body dementia
• 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
• 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
• Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue PloS one · 2010-10-11 · usefulness score 55/100 · Lewy body dementia
• An acetylation switch controls TDP-43 function and aggregation propensity Nature communications · 2015-01-05 · usefulness score 54/100 · Lewy body dementia

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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.

• 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
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