Suppression of Parkin enhances nigrostriatal and motor neuron lesion in mice over-expressing human-mutated tau protein

Abstract

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-/-+tau(VLW) 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-/-+tau(VLW) mice could be useful for testing of compounds with putative therapeutic value in human tauopathies.

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

“…It combines several potential neuroprotective effects, such as the stimulation of both CB1 and CB2 receptors by THC with the antioxidant effects of CBD [24]. Sativex ® is therefore especially adequate for the study of neuroprotective effects of cannabinoids on PK −/− /Tau VLW mice, a complex model of tauopathy, which has been previously described [25] and which combines cerebral and peripheral deposition of amyloid with lesions of the hippocampus, substantia nigra, and lower motor neuron and resembles a multisystemic neurological disease such as frontotemporal dementia with parkinsonism and amyotrophy [25][26][27][28]. These mice have lower levels of c-terminal HSP70 interacting protein (CHIP-HSP70), involved in the proteosomal degradation of tau, increased oxidative stress, measured as depletion of glutathione which, added to lack of parkin, could trigger tau accumulation and amyloidogenesis.…”

“…PK −/− /Tau VLW mice provide a link between the two proteins more important for the pathogenesis of Alzheimer's disease [25][26][27][28].…”

“…Our experiments were performed on littermates generated by a heterozygote intercross of human-mutated tau overexpressing mice (Tau VLW ), overexpressing a human four-repeat tau isoform carrying three mutations (G272V, P301L, and R406W) linked to frontotemporal dementia FTD-17 and the parkin-null mutant mice (PK −/− ) as previously described [25,26]. Mice were obtained by breeding the animals according to the schema shown in Supplementary Figure 1 (available online: http://www.j-alz.com/issues/35/vol35-3.html#supplementarydata02).…”

“…For PCR, 150 ng of genomic DNA was denatured for 3 min at 94 • C and subjected to 35 Twenty-microliter volumes of PCR products were analyzed by electrophoresis on a 1.8% agarose gel that was subsequently stained with ethidium bromide for visualization of DNA bands. DNA molecular weight markers (Roche, Spain) were used to provide a size reference for the test reactions [25,26].…”

“…After decapitation, the brains were dissected as described [26]. The limbic, striatum, and midbrain brain regions were frozen on dry ice and the levels of monoamines and their metabolites were measured by HPLC with an ESA coulochem detector [26].…”