TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration

Topic: Brain proteins, microglia and lab models

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that show considerable clinical and pathologic overlap, with no effective treatments available. Mutations in the RNA binding protein TDP-43 were recently identified in patients with familial amyotrophic lateral sclerosis (ALS), and TDP-43 aggregates are found in both ALS and FTLD-U (FTLD with ubiquitin aggregates), suggesting a common underlying mechanism. We report that mice expressing a mutant form of human TDP-43 develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and FTLD-U. Despite universal transgene expression throughout the nervous system, pathologic aggregates of ubiquitinated proteins accumulate only in specific neuronal populations, including layer 5 pyramidal neurons in frontal cortex, as well as spinal motor neurons, recapitulating the phenomenon of selective vulnerability seen in patients with FTLD-U and ALS. Surprisingly, cytoplasmic TDP-43 aggregates are not present, and hence are not required for TDP-43-induced neurodegeneration. These results indicate that the cellular and molecular substrates for selective vulnerability in FTLD-U and ALS are shared between mice and humans, and suggest that altered DNA/RNA-binding protein function, rather than toxic aggregation, is central to TDP-43-related neurodegeneration.

Key findings

• These results indicate that the cellular and molecular substrates for selective vulnerability in FTLD-U and ALS are shared between mice and humans, and suggest that altered DNA/RNA-binding protein function, rather than toxic aggregation, is central to TDP-43-related neurodegeneration.

Why it matters

Mice expressing mutant human TDP-43 developed a progressive fatal disease resembling ALS and FTLD-U, yet cytoplasmic TDP-43 aggregates were absent. This animal work suggests altered protein function rather than aggregation drives disease, and no treatment was tested.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1073/pnas.0908767106
• PubMed: 19833869
• 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{wegorzewska2009-19833869,
  author  = {Wegorzewska, I. and Bell, S. and Cairns, N. J. and Miller, T. M. and Baloh, R. H.},
  title   = {{TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration}},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year    = {2009},
  doi     = {10.1073/pnas.0908767106},
  pmid    = {19833869},
  url     = {https://doi.org/10.1073/pnas.0908767106}
}

Studies this one cites

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• 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
• 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
• The overlap of amyotrophic lateral sclerosis and frontotemporal dementia Neurology · 2002-10-01 · usefulness score 59/100 · Getting a diagnosis
• Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration Acta neuropathologica · 2007-06-20 · usefulness score 59/100 · Getting a diagnosis
• 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
• Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43 Acta neuropathologica · 2007-01-12 · usefulness score 54/100 · Brain tissue and pathology
• 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
• 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
• The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases The EMBO journal · 2008-01-01 · usefulness score 49/100 · Lewy body dementia
• Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity Brain : a journal of neurology · 1991-04-01 · usefulness score 48/100 · Disparities

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