Human Molecular Genetics Advance Access originally published online on May 12, 2006
Human Molecular Genetics 2006 15(13):2045-2058; doi:10.1093/hmg/ddl129
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Suppression of Parkin enhances nigrostriatal and motor neuron lesion in mice over-expressing human-mutated tau protein
1 Servicio de Neurobiología, Departamento de Investigación (-1D) Hospital Ramón y Cajal, 2 Banco de Tejidos para Investigaciones Neurológicas, 3 Laboratorio de Neurología, Fundación Jiménez Díaz, 4 Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Consejo Superior de Investigaciones Científicas, Spain and 5 Servicio de Neurología Hospital Ramón y Cajal Ctra. de Colmenar, Km. 9, Madrid 28034, Spain
* To whom correspondence should be addressed. Tel: +34 913368384; fax: +34 913369016; Email: maria.a.mena{at}hrc.es
Received January 27, 2006; Accepted May 10, 2006
Abnormal deposition of protein tau takes place in the brain of patients with several neurodegenerative diseases. Few of these patients present frontotemporal dementia with parkinsonism and amyotrophy (FTDPA-17), an autosomal dominant tauopathy related to mutations of the gene that codes for protein tau, localized in chromosome 17. The great majority of patients with tauopathies such as Alzheimer's disease, sporadic frontotemporal dementia or progressive supranuclear palsy do not show a Mendelian pattern of inheritance. We have occasionally seen tauopathies in patients with parkin mutations and, therefore, hypothesized that the protein tau interacts with parkin. We have tested that hypothesis in mice with combined genetic modifications of tau (over-expression of human tau with three mutations known to produce FTDPA-17) and parkin (deleted) proteins. Homozygote parkin null or over-expressing mutated-human tau mice have subtle behavioral and molecular abnormalities but do not express a clinical phenotype of neurodegenerative disease. Mice with combined homozygous mutations of these two genes show progressively abnormal walking already noticeable at 3 months of age, loss of dopamine and dopamine markers in striatum, nuclear tau immunoreactive deposits in motor neurons of the spinal cord, abnormal expression of glial markers and enhanced levels of pro-apoptotic proteins; findings that were absent or less pronounced in homozygote animals with deletions of parkin or over-expression of tau. The double transgenic mice do not express normal mechanisms of adaptation to stress such as increased levels of GSH and Hsp-70. In addition, they have reduced levels of CHIP–Hsc70, a complex known to attenuate aggregation of tau and to enhance ubiquitination of phosphorylated tau. We have found high levels of phosphorylated tau in parkin–/–+tauVLW mice and a relative decrease of the inactivated pSer9 to total GSK-3 levels. Our data reveal that there are interactions between tau and parkin that could be relevant for the pathogenesis and treatment of tauopathies. Similarly, we hope that the double transgenic parkin–/–+tauVLW mice could be useful for testing of compounds with putative therapeutic value in human tauopathies.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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