Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson’s disease

Abstract

Although clinically distinct diseases, tauopathies and synucleinopathies share 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 PDGF 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 p-GSK-3β, a major kinase involved in hyperphosphorylation of Tau. Differential Triton X-100 extraction of striata showed the presence of aggregated α-Syn in the Tg mice, along with p-Tau and p-GSK-3β, which was also confirmed through immunohistochemistry. After p-Tau formation, both Tau and MAP1 dissociated from the cytoskeleton, consistent with 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 PDGF-α-synuclein mice provides further confirmation that Parkinson's may be a tauopathic disease. KeywordsAlzheimer's disease; neurodegeneration; synucleinopathies; tauopathies Sporadic Parkinson's disease [PD] is a progressive neurodegenerative disease of unknown etiology [Pollanen et al, 1993], resulting in loss of motor function and degeneration of dopaminergic neurons [Pollanen et al, 1993;Jakes et al, 1994;Forno, 1996;Spillantini et al, 1998;Corti et al 2005]. Alpha-synuclein [α-Syn], a presynaptic protein, is causal in the genesis of PD [Forno, 1996;Spillantini et al, 1998], and gene duplication and triplication of α-Syn are found in sporadic and early onset forms of PD [Singleton et al, 2003] NIH Public Access Author ManuscriptEur J Neurosci. Author manuscript; available in PMC 2012 May 1. A53T and E46K] in the gene are linked to autosomal dominant familial forms of the disease [Polymeropoulos et al, 1997;Kruger et al, 1998]. Although a soluble protein, under pathological conditions, α-Syn becomes insoluble, self-aggregates and accumulates into intra-neuronal inclusion bodies [Spillantini et al, 1998;Masliah et al, 2000;El-Agnaf et al, 1998;Gosavi et al, 2002]. Similar to α-Syn, Tau is also a highly soluble protein that becomes insoluble by pathological hyperphosphorylation, leading to tauopathies, including Alzheimer's disease (AD), [Dickson et al, 2002;Esper et al, 2007;Gasparini et al, 2007;Wadia & Lang, 2007;Gong & Iqba...

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

“…25,26 The aforementioned studies combined with our current results suggest that hyperactivation of GSK-3β may be the primary mechanism by which this protein is linked to PD (Figure 7). Indeed, a growing body of evidence from our laboratory and others define the important roles, kinases, such as GSK-3β, CK2, PLK2 and 3, and GRK1-5 have in the development and pathology of PD through the phosphorylation of α-Syn and Tau 16,[18][19][20][21][22][23][24][53][54][55][56][57] (Supplementary Table S3 and associated references).…”

“…11 We 12,13 and others 14,15 have also identified p-Tau in different brain regions of PD, dementia with Lewy bodies, and AD. High levels of p-Tau have also been observed in vivo in several toxin [16][17][18] and transgenic α-Syn models of PD, 19,20 suggesting that p-Tau may be an important common factor in the neurodegeneration of not only tauopathies but also of synucleinopathies, such as PD. [21][22][23][24] Most studies to date have focused on the formation and accumulation of Tau and p-Tau in idiopathic PD.…”

“…Tissues were prepared as previously described. 12,19,20 See supplementary material and methods for further details.…”

“…12,13,16,19,20 In in vitro studies of MPTPtreated SH-SY5Y cells, blockade of GSK-3β with lithium, or with the highly selective non-ATP competitive inhibitor, TDZD--8, prevented the induction of p-GSK-3β-Y216, abolished p-Tau formation, and reversed the accumulation and aggregation of both p-Tau and α-Syn, averting cell death. 16 Other studies using Rotenone or MPTP/MPP+ in chemical PD models, have shown similar results of decreased neuronal viability during treatments accompanied by dose-and timedependent increases in GSK-3β activation, with decreased cytotoxicity detected when GSK-3β was inhibited or knockeddown through the use of GSK-3β-specific small molecule inhibitors or through RNAi.…”

The role of α-synuclein in neurodegeneration — An update

“…Cellular, various tg and other experimental PD models provided new insight in the hyperphosphorylation of tau [566,569,[576][577][578][579][580]. They suggest that oxidatively modified AS is degraded by the proteasome and plays a pro-aggretatory role for tau [581], and that AS is an in vivo regulator for tau phosphorylation at Ser 262 leading to deposition of both proteins [582].…”