Tauopathic Changes in the Striatum of A53T α-Synuclein Mutant Mouse Model of Parkinson's Disease

Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the alpha-synuclein (alpha-Syn) A53T mutant mouse. Elevated levels of alpha-Syn were observed in striatum of the adult A53T alpha-Syn mice. This was accompanied by increases in hyperphosphorylated Tau [ p-Tau], phosphorylated at Ser202, Ser262 and Ser396/404, which are the same toxic sites also seen in Alzheimer's disease. There was an increase in active p-GSK-3 beta, hyperphosphorylated at Tyr216, a major and primary kinase known to phosphorylate Tau at multiple sites. The sites of hyperphosphorylation of Tau in the A53T mutant mice were similar to those seen in post-mortem striata from PD patients, attesting to their pathophysiological relevance. Increases in p-Tau were not due to alterations on protein phosphatases in either A53T mice or in human PD, suggesting lack of involvement of these proteins in tauopathy. Extraction of striata with Triton X-100 showed large increases in oligomeric forms of alpha-Syn suggesting that alpha-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3 beta and pSer396/404 were also found associated with aggregated alpha-Syn. Differential solubilization to measure protein binding to cytoskeletal proteins demonstrated that p-Tau in the A53T mutant mouse were unbound to cytoskeletal proteins, consistent with dissociation of p-Tau from the microtubules upon hyperphosphorylation. Interestingly, alpha-Syn remained tightly bound to the cytoskeleton, while p-GSK-3 beta was seen in the cytoskeleton-free fractions. Immunohistochemical studies showed that alpha-Syn, pSer396/404 Tau and p-GSK-3 beta co-localized with one another and was aggregated and accumulated into large inclusion bodies, leading to cell death of Substantia nigral neurons. Together, these data demonstrate an elevated state of tauopathy in striata of the A53T alpha-Syn mutant mice, suggesting that tauopathy is a common feature of synucleinopathies.