Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>α-Synuclein aggregates in Lewy bodies and plays a central role in the pathogenesis of a group of neurodegenerative disorders, known as "Synucleinopathies", including Parkinson's disease. Parkin mutations result in loss of parkin E3-ubiquitin ligase activity and cause autosomal recessive early onset parkinsonism.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We tested how these two genes interact by examining the effects of parkin on post-translational modification of α-Synuclein in gene transfer animal models, using a lentiviral gene delivery system into the striatum of 2-month old male Sprague Dawley rats.</jats:p> <jats:p>Viral expression of wild type α-Synuclein caused accumulation of α-Synuclein and was associated with increased cell death and inflammation. α-Synuclein increased PLK2 levels and GSK-3β activity and increased the levels of phosphorylated α-Synuclein and Tau. Parkin co-expression reduced the levels of phosphorylated α-Synuclein and attenuated cell death and inflammation. Parkin reduced PLK2 levels and increased PP2A activation.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These data suggest that parkin reduces α-Synuclein levels and alters the balance between phosphatase and kinase activities that affect the levels of phosphorylated α-Synuclein. These results indicate novel mechanisms for parkin protection against α-Synuclein-induced toxicity in PD.</jats:p> </jats:sec>