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

Preeti J. Khandelwal, Sonya B. Dumanis, Li Rebekah Feng, Kathleen Maguire-Zeiss, Gw Rebeck, Hilal A. Lashuel, Charbel Eh Moussa

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Abstract

Background. 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. Results. 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. 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-3 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. Conclusions. 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.

Original languageEnglish
Article number47
JournalMolecular Neurodegeneration
Volume5
Issue number1
DOIs
Publication statusPublished - 9 Nov 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Khandelwal, P. J., Dumanis, S. B., Feng, L. R., Maguire-Zeiss, K., Rebeck, G., Lashuel, H. A., & Moussa, C. E. (2010). Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model. Molecular Neurodegeneration, 5(1), [47]. https://doi.org/10.1186/1750-1326-5-47