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

Research output: Contribution to journalArticle

43 Citations (Scopus)

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

Fingerprint

Synucleins
Phosphorylation
Genes
Cell Death
Inflammation
Glycogen Synthase Kinase 3
Lewy Bodies
Gene Transfer Techniques
Ubiquitin-Protein Ligases
Parkinsonian Disorders
Post Translational Protein Processing
Phosphoric Monoester Hydrolases
Neurodegenerative Diseases
Sprague Dawley Rats
Parkinson Disease
Phosphotransferases
Animal Models

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

Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model. / Khandelwal, Preeti J.; Dumanis, Sonya B.; Feng, Li Rebekah; Maguire-Zeiss, Kathleen; Rebeck, Gw; Lashuel, Hilal A.; Moussa, Charbel Eh.

In: Molecular Neurodegeneration, Vol. 5, No. 1, 47, 09.11.2010.

Research output: Contribution to journalArticle

Khandelwal, PJ, Dumanis, SB, Feng, LR, Maguire-Zeiss, K, Rebeck, G, Lashuel, HA & Moussa, CE 2010, 'Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model', Molecular Neurodegeneration, vol. 5, no. 1, 47. https://doi.org/10.1186/1750-1326-5-47
Khandelwal PJ, Dumanis SB, Feng LR, Maguire-Zeiss K, Rebeck G, Lashuel HA et al. Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model. Molecular Neurodegeneration. 2010 Nov 9;5(1). 47. https://doi.org/10.1186/1750-1326-5-47
Khandelwal, Preeti J. ; Dumanis, Sonya B. ; Feng, Li Rebekah ; Maguire-Zeiss, Kathleen ; Rebeck, Gw ; Lashuel, Hilal A. ; Moussa, Charbel Eh. / Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model. In: Molecular Neurodegeneration. 2010 ; Vol. 5, No. 1.
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