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The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model.

Publication ,  Journal Article
Dawson, HN; Cantillana, V; Chen, L; Vitek, MP
Published in: J Neurosci
August 22, 2007

Intracellular tau deposits are characteristic of several neurodegenerative disorders called tauopathies. The tau protein regulates the stability and assembly of microtubules by binding to microtubules through three or four microtubule-binding repeats (3R and 4R). The number of microtubule-binding repeats is determined by the inclusion or exclusion of the second microtubule-binding repeat encoded by exon 10 of the TAU gene. TAU gene mutations that alter the inclusion of exon 10, and hence the 4R:3R ratio, are causal in the tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). A mutation located in exon 10 has been identified in several FTDP-17 families that present with increased exon 10 inclusion in both mRNA and protein, parkinsonism, movement disorders, and dementia. We have engineered a human tau minigene construct that was designed to allow alternative splicing of the tau exon 10. Here we demonstrate that transgenic mice expressing human tau protein with this mutation develop neurodegeneration as result of aberrant splicing. The mice recapitulate many of the disease hallmarks that are seen in patients with this mutation, including increased tau exon 10 inclusion in both mRNA and protein, motor and behavioral deficits, and tau protein accumulation in neurons and tufted astrocytes. Furthermore, these mice present with degeneration of the nigrostriatal dopaminergic pathway, suggesting a possible mechanism for parkinsonism in FTDP-17. Additionally, activated caspase-3 immunoreactivity in both neurons and astrocytes implicates the involvement of the apoptotic pathway in the pathology of these mice.

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Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

August 22, 2007

Volume

27

Issue

34

Start / End Page

9155 / 9168

Location

United States

Related Subject Headings

  • tau Proteins
  • RNA Splicing
  • Parkinsonian Disorders
  • Neurons
  • Neurology & Neurosurgery
  • Nerve Tissue Proteins
  • Motor Activity
  • Models, Molecular
  • Mice, Transgenic
  • Mice
 

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Dawson, H. N., Cantillana, V., Chen, L., & Vitek, M. P. (2007). The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model. J Neurosci, 27(34), 9155–9168. https://doi.org/10.1523/JNEUROSCI.5492-06.2007
Dawson, Hana N., Viviana Cantillana, Liling Chen, and Michael P. Vitek. “The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model.J Neurosci 27, no. 34 (August 22, 2007): 9155–68. https://doi.org/10.1523/JNEUROSCI.5492-06.2007.
Dawson, Hana N., et al. “The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model.J Neurosci, vol. 27, no. 34, Aug. 2007, pp. 9155–68. Pubmed, doi:10.1523/JNEUROSCI.5492-06.2007.

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

August 22, 2007

Volume

27

Issue

34

Start / End Page

9155 / 9168

Location

United States

Related Subject Headings

  • tau Proteins
  • RNA Splicing
  • Parkinsonian Disorders
  • Neurons
  • Neurology & Neurosurgery
  • Nerve Tissue Proteins
  • Motor Activity
  • Models, Molecular
  • Mice, Transgenic
  • Mice