Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson’s disease
- 1 April 2011
- journal article
- Published by Wiley in European Journal of Neuroscience
- Vol. 33 (9), 1598-1610
- https://doi.org/10.1111/j.1460-9568.2011.07660.x
Abstract
Although clinically distinct diseases, tauopathies and synucleinopathies share a common genesis and mechanisms, leading to overlapping degenerative changes within neurons. In human postmortem striatum of Parkinson’s disease (PD) and PD with dementia, we have recently described elevated levels of tauopathy, indexed as increased hyperphosphorylated Tau (p‐Tau). Here we assessed tauopathy in striatum of a transgenic animal model of PD, overexpressing human α‐synuclein under the platelet‐derived growth factor promoter. At 11 months of age, large and progressive increases in p‐Tau in transgenic mice, hyperphosphorylated at sites reminiscent of Alzheimer’s disease, were noted, along with elevated levels of α‐synuclein and glycogen synthase kinase 3β phosphorylated at Tyr216 (p‐GSK‐3β), a major kinase involved in the hyperphosphorylation of Tau. Differential Triton X‐100 extraction of striata showed the presence of aggregated α‐synuclein in the transgenic mice, along with p‐Tau and p‐GSK‐3β, which was also confirmed through immunohistochemistry. After p‐Tau formation, both Tau and microtubule‐associated protein 1 (MAP1) dissociated from the cytoskeleton, consistent with the diminished ability of these cytoskeleton‐binding proteins to bind microtubules. Increases in free tubulin and actin were also noted, indicative of cytoskeleton remodeling and destabilization. In vivo magnetic resonance imaging of the transgenic animals showed a reduction in brain volume of transgenic mice, indicating substantial atrophy. From immunohistochemical studies, α‐synuclein, p‐Tau and p‐GSK‐3β were found to be overexpressed and co‐localized in large inclusion bodies, reminiscent of Lewy bodies. The elevated state of tauopathy seen in these platelet‐derived growth factor–α‐synuclein mice provides further confirmation that PD may be a tauopathic disease.Keywords
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