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

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], while mutations [A30P, 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 & Iqbal, 2008; Ling et al, 2010; Ludolph et al, 2009; Williams & Lees, 2009]. Whereas both primary synucleinopathies and tauopathies have distinct clinical features, significant overlap exists between these neurodegenerative diseases, particularly manifest in the variable co-morbidity of dementia and Parkinsonism [Murray et al, 2005]. Moreover, p-Tau is often found in Lewy bodies in PD, while α-Syn pathology is seen in Alzheimer’s disease [Crews et al, 2009]. There is increasing evidence that suggests a direct interaction between these proteins [Giasson et al, 2003]. Using the MPTP mouse neurotoxin model of PD, we recently demonstrated that increases in α-Syn can initiate and sustain Tau hyperphosphorylation in vivo and in vitro [Duka et al, 2006; Duka & Sidhu, 2006; Kozikowski et al, 2006; Duka et al, 2009]. The hyperphosphorylation of Tau was absolutely dependent on the presence of α-Syn, as indexed by lack of p-Tau formation in MPTP-treated α-Syn−/− mice or in cells lacking α-Syn. Our more recent studies indicates that α-Syn induces p-Tau formation through specific activation and recruitment of p-GSK-3β, a kinase known to hyperphosphorylate Tau at distinct sites in AD, which itself becomes activated through autophosphorylation at Tyr216 [Duka et al, 2009]. Importantly, we also found tauopathy in postmortem brains of PD and PDD patients, where we found high levels of p-Tau, α-Syn and p-GSK-3β in striatum, but not in the inferior frontal gyrus, suggesting a different anatomical distribution of Tau pathology in PD patients as compared to AD patients [Wills et al, 2010]. In the current study, we have investigated the state of tauopathy in a transgenic mouse model of PD that over-expresses the human α-Syn transgene under the control of the platelet derived growth factor [PDGF] promoter [Rockenstein et al, 2002]. Our results indicate a spontaneous age-dependent development of tauopathy in these mice, and provide further support for the concept that PD is a form of tauopathy.