Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia

Ittner, Lars M., Fath, Thomas, Ke, Yazi D., Bi, Mian, van Eersel, Janet, Li, Kong M., Gunning, Peter and Gotz, Jurgen (2008) Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. Proceedings of the National Academy of Sciences of the United States of America, 105 41: 15997-16002. doi:10.1073/pnas.0808084105


Author Ittner, Lars M.
Fath, Thomas
Ke, Yazi D.
Bi, Mian
van Eersel, Janet
Li, Kong M.
Gunning, Peter
Gotz, Jurgen
Title Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2008-10-14
Sub-type Article (original research)
DOI 10.1073/pnas.0808084105
Volume 105
Issue 41
Start page 15997
End page 16002
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Abstract Frontotemporal dementia (FTD) is characterized by cognitive and behavioral changes and, in a significant subset of patients, Parkinsonism. Histopathologically, FTD frequently presents with tau-containing lesions, which in familial cases result from mutations in the MAPT gene encoding tau. Here we present a novel transgenic mouse strain (K3) that expresses human tau carrying the FTD mutation K369I. K3 mice develop a progressive histopathology that is reminiscent of that in human FTD with the K369I mutation. In addition, K3 mice show early-onset memory impairment and amyotrophy in the absence of overt neurodegeneration. Different from our previously generated tau transgenic strains, the K3 mice express the transgene in the substantia nigra (SN) and show an early-onset motor phenotype that reproduces Parkinsonism with tremor, bradykinesia, abnormal gait, and postural instability. Interestingly, motor performance of young, but not old, K3 mice improves upon L-dopa treatment, which bears similarities to Parkinsonism in FTD. The early-onset symptoms in the K3 mice are mechanistically related to selectively impaired anterograde axonal transport of distinct cargos, which precedes the loss of dopaminergic SN neurons that occurs in aged mice. The impaired axonal transport in SN neurons affects, among others, vesicles containing the dopamine-synthesizing enzyme tyrosine hydroxylase. Distinct modes of transport are also impaired in sciatic nerves, which may explain amyotrophy. Together, the K3 mice are a unique model of FTD-associated Parkinsonism, with pathomechanistic implications for the human pathologic process.
Keyword Alzheimer
Memory
NFT
Tau
Transgenic
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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