tauopathic changes in the striatum of a53t α-synuclein mutant mouse model of parkinsons diseasetauopathic纹状体的变化a53tα-synuclein帕金森疾病的突变小鼠模型.pdfVIP

Tauopathic Changes in the Striatum of A53T a-Synuclein Mutant Mouse Model of Parkinson’s Disease Jonathan Wills, Joel Credle, Thomas Haggerty, Jae-Hoon Lee, Adam W. Oaks, Anita Sidhu* Department of Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, D.C., United States of America Abstract 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 a- synuclein (a-Syn) A53T mutant mouse. Elevated levels of a-Syn were observed in striatum of the adult A53T a-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-3b, 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 a-Syn suggesting that a-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3b and pSer396/404 were also found associated with aggregated a-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