PMID- 17715352
OWN - NLM
STAT- MEDLINE
DCOM- 20070911
LR  - 20200225
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 27
IP  - 34
DP  - 2007 Aug 22
TI  - The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and 
      parkinsonism linked to chromosome 17 tauopathy in a mouse model.
PG  - 9155-68
AB  - 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.
FAU - Dawson, Hana N
AU  - Dawson HN
AD  - Division of Neurology, Duke University, Durham, North Carolina 27710, USA. 
      dawso009@mc.duke.edu
FAU - Cantillana, Viviana
AU  - Cantillana V
FAU - Chen, Liling
AU  - Chen L
FAU - Vitek, Michael P
AU  - Vitek MP
LA  - eng
GR  - R01 AG019780/AG/NIA NIH HHS/United States
GR  - 5R01-AG19780-05/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (tau Proteins)
RN  - 7006-34-0 (Asparagine)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Age Factors
MH  - Analysis of Variance
MH  - Animals
MH  - Asparagine/*genetics
MH  - Behavior, Animal
MH  - Central Nervous System/pathology
MH  - Chromosomes, Human, Pair 17/*genetics
MH  - Dementia/*genetics
MH  - Embryo, Mammalian
MH  - Exons/genetics
MH  - Gene Expression Regulation, Developmental
MH  - Humans
MH  - Lysine/*genetics
MH  - Maze Learning/physiology
MH  - Mice
MH  - Mice, Transgenic
MH  - Models, Molecular
MH  - Motor Activity/genetics
MH  - Nerve Tissue Proteins/metabolism
MH  - Neurons/metabolism
MH  - Parkinsonian Disorders/*genetics
MH  - RNA Splicing/*genetics
MH  - tau Proteins/*genetics
PMC - PMC6672194
EDAT- 2007/08/24 09:00
MHDA- 2007/09/12 09:00
PMCR- 2008/02/22
CRDT- 2007/08/24 09:00
PHST- 2007/08/24 09:00 [pubmed]
PHST- 2007/09/12 09:00 [medline]
PHST- 2007/08/24 09:00 [entrez]
PHST- 2008/02/22 00:00 [pmc-release]
AID - 27/34/9155 [pii]
AID - 3255676 [pii]
AID - 10.1523/JNEUROSCI.5492-06.2007 [doi]
PST - ppublish
SO  - J Neurosci. 2007 Aug 22;27(34):9155-68. doi: 10.1523/JNEUROSCI.5492-06.2007.