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

• DOI: 10.1073/pnas.0808084105
• Publication Date: 2008-10-03T00:25:36Z
• Authors: Lars M. Ittner; Thomas Fath; Yazi D. Ke; Mian Bi; Janet van Eersel; Kong M. Li; Peter Gunning; Jürgen Götz
• Keywords: Axoplasmic transport

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 familial cases result from mutations the MAPT gene encoding tau. Here we present novel transgenic mouse strain (K3) that expresses human tau carrying mutation K369I. K3 mice develop progressive histopathology reminiscent K369I mutation. In addition, show early-onset memory impairment amyotrophy absence overt neurodegeneration. Different our previously generated strains, express transgene substantia nigra (SN) an motor phenotype reproduces Parkinsonism tremor, bradykinesia, abnormal gait, postural instability. Interestingly, performance young, but not old, improves upon L-dopa treatment, bears similarities to FTD. The symptoms are mechanistically related selectively impaired anterograde axonal transport distinct cargos, precedes loss dopaminergic SN neurons occurs aged mice. affects, among others, vesicles containing dopamine-synthesizing enzyme tyrosine hydroxylase. Distinct modes also sciatic nerves, may explain amyotrophy. Together, unique model FTD-associated Parkinsonism, pathomechanistic implications for pathologic process.