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In Vivo Modulation of Polo-Like Kinases (PLK) Supports a Key Role for PLK2 in Ser129 ?-Synuclein Phosphorylation in Mouse Brain.
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Neuroscience 2013 Oct;
Authors: Marcelle Bergeron, Ruth Motter, Pearl Tanaka, Donald Fauss, Michael Babcock, San-San Chiou, Seth Nelson, Florentino San Pablo, John P Anderson
Departments of Pharmacological Sciences, Elan Pharmaceuticals, South San Francisco, CA, 94080 U.S.A. Electronic address: email@example.com.
?-Synuclein is the major component of Lewy bodies. ?-Synuclein phosphorylated at Ser 129 (Phospho ?-Syn) is the most common synuclein modification observed in Parkinson's disease pathology and transgenic animal models. PLK2 was previously proposed as an important kinase in ?-synuclein phosphorylation at Ser129. To better understand the role of PLK2 in ?-synuclein phosphorylation in vivo, we further evaluated the effect of PLK2 genetic knockdown and pharmacological inhibition on Phospho ?-Syn levels in different brain regions of PLK2 knockout (KO), heterozygous (Het) and wild-type (WT) mice. Whereas PLK2 knockdown had no effect on Total ? -synuclein brain levels, it resulted in a gene-dosage dependent, albeit incomplete, reduction of endogenous Phospho ?-Syn levels in all brain regions investigated. No compensatory induction of other ?-synuclein kinases (PLK3, casein kinase-2, GRK5 and GRK6) was observed at the mRNA level in PLK2 KO mouse brain. To determine whether increased activity of another PLK family member is responsible for the residual Phospho ?-Syn levels in PLK2 KO mouse brain, the pan-PLK inhibitor BI 2536 was tested in PLK2 KO mice. Whereas BI 2536 reduced Phospho ?-Syn levels in WT mice, it did not further reduce the residual endogenous Phospho ?-Syn levels in PLK2 KO and Het mice, suggesting that a kinase other than PLK1-3 accounts for the remaining PLK inhibitor-resistant pool in mouse brain. Moreover, PLK3 KO in mice had no effect on both Total- and Phospho- ?-Syn brain levels. These results support a significant role for a PLK kinase in phosphorylating ?-synuclein at Ser129 in the brain, and suggest that PLK2 is responsible for this activity under physiological conditions.
PMID: 24128992 [PubMed - as supplied by publisher]