Polo-like Kinase 2 (PLK2) Phosphorylates Alpha-synuclein at Serine 129 in Central Nervous System

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2008 Nov 14

PMID 19004816

Citations 127

Authors

Kelly J Inglis

David Chereau

Elizabeth F Brigham

San-San Chiou

Susanne Schobel

Normand L Frigon

Mei Yu

Russell J Caccavello

Seth Nelson

Ruth Motter

Sarah Wright

David Chian

Pamela Santiago

Ferdie Soriano

Carla Ramos

Kyle Powell

Jason M Goldstein

Michael Babcock

Ted Yednock

Frederique Bard

Guriqbal S Basi

Hing Sham

Tamie J Chilcote

Lisa McConlogue

Irene Griswold-Prenner

John P Anderson

Affiliations

Soon will be listed here.

Abstract

Several neurological diseases, including Parkinson disease and dementia with Lewy bodies, are characterized by the accumulation of alpha-synuclein phosphorylated at Ser-129 (p-Ser-129). The kinase or kinases responsible for this phosphorylation have been the subject of intense investigation. Here we submit evidence that polo-like kinase 2 (PLK2, also known as serum-inducible kinase or SNK) is a principle contributor to alpha-synuclein phosphorylation at Ser-129 in neurons. PLK2 directly phosphorylates alpha-synuclein at Ser-129 in an in vitro biochemical assay. Inhibitors of PLK kinases inhibited alpha-synuclein phosphorylation both in primary cortical cell cultures and in mouse brain in vivo. Finally, specific knockdown of PLK2 expression by transduction with short hairpin RNA constructs or by knock-out of the plk2 gene reduced p-Ser-129 levels. These results indicate that PLK2 plays a critical role in alpha-synuclein phosphorylation in central nervous system.

Citing Articles

The Interplay of Stress, Inflammation, and Metabolic Factors in the Course of Parkinson's Disease.

Ben Shaul T, Frenkel D, Gurevich T Int J Mol Sci. 2024; 25(22).

PMID: 39596474 PMC: 11594997. DOI: 10.3390/ijms252212409.

Pharmacological inhibition of PLK2 kinase activity mitigates cognitive decline but aggravates APP pathology in a sex-dependent manner in APP/PS1 mouse model of Alzheimer's disease.

Martinez-Drudis L, Berard M, Musiol D, Rivest S, Oueslati A Heliyon. 2024; 10(20):e39571.

PMID: 39498012 PMC: 11532864. DOI: 10.1016/j.heliyon.2024.e39571.

Polo-like kinase inhibition leads to neuroprotection of neurons bearing alpha-synuclein Lewy body-like inclusions .

Rose E, Banga J, Unni V MicroPubl Biol. 2024; 2024.

PMID: 39464295 PMC: 11507930. DOI: 10.17912/micropub.biology.001348.

The role of polo-like kinases 2 in the proteasomal and lysosomal degradation of alpha-synuclein in neurons.

Sung C, Lam W, Chung K FASEB J. 2024; 38(20):e70121.

PMID: 39436202 PMC: 11580719. DOI: 10.1096/fj.202401035R.

Imaging spatial transcriptomics reveals molecular patterns of vulnerability to pathology in a transgenic α-synucleinopathy model.

Horan-Portelance L, Iba M, Acri D, Gibbs J, Cookson M bioRxiv. 2024; .

PMID: 39372781 PMC: 11451628. DOI: 10.1101/2024.07.31.606032.

References

Simmons D, Neel B, Stevens R, Evett G, Erikson R . Identification of an early-growth-response gene encoding a novel putative protein kinase. Mol Cell Biol. 1992; 12(9):4164-9. PMC: 360319. DOI: 10.1128/mcb.12.9.4164-4169.1992. View

Kahle P, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W . Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep. 2002; 3(6):583-8. PMC: 1084143. DOI: 10.1093/embo-reports/kvf109. View

Chen L, Feany M . Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci. 2005; 8(5):657-63. DOI: 10.1038/nn1443. View

Spillantini M, Crowther R, Jakes R, Hasegawa M, Goedert M . alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc Natl Acad Sci U S A. 1998; 95(11):6469-73. PMC: 27806. DOI: 10.1073/pnas.95.11.6469. View

Spillantini M, Schmidt M, Lee V, Trojanowski J, Jakes R, Goedert M . Alpha-synuclein in Lewy bodies. Nature. 1997; 388(6645):839-40. DOI: 10.1038/42166. View

Pak D, Sheng M . Targeted protein degradation and synapse remodeling by an inducible protein kinase. Science. 2003; 302(5649):1368-73. DOI: 10.1126/science.1082475. View

Okochi M, Walter J, Koyama A, Nakajo S, Baba M, Iwatsubo T . Constitutive phosphorylation of the Parkinson's disease associated alpha-synuclein. J Biol Chem. 2000; 275(1):390-7. DOI: 10.1074/jbc.275.1.390. View

Zarranz J, Alegre J, Gomez-Esteban J, Lezcano E, Ros R, Ampuero I . The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004; 55(2):164-73. DOI: 10.1002/ana.10795. View

Seeburg D, Sheng M . Activity-induced Polo-like kinase 2 is required for homeostatic plasticity of hippocampal neurons during epileptiform activity. J Neurosci. 2008; 28(26):6583-91. PMC: 3844828. DOI: 10.1523/JNEUROSCI.1853-08.2008. View

10.

Freichel C, Neumann M, Ballard T, Muller V, Woolley M, Ozmen L . Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice. Neurobiol Aging. 2006; 28(9):1421-35. DOI: 10.1016/j.neurobiolaging.2006.06.013. View

11.

Gorbatyuk O, Li S, Sullivan L, Chen W, Kondrikova G, Manfredsson F . The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease. Proc Natl Acad Sci U S A. 2008; 105(2):763-8. PMC: 2206610. DOI: 10.1073/pnas.0711053105. View

12.

Waxman E, Giasson B . Specificity and regulation of casein kinase-mediated phosphorylation of alpha-synuclein. J Neuropathol Exp Neurol. 2008; 67(5):402-16. PMC: 2930078. DOI: 10.1097/NEN.0b013e31816fc995. View

13.

Ellis C, Schwartzberg P, Grider T, Fink D, Nussbaum R . alpha-synuclein is phosphorylated by members of the Src family of protein-tyrosine kinases. J Biol Chem. 2000; 276(6):3879-84. DOI: 10.1074/jbc.M010316200. View

14.

Baba M, Nakajo S, Tu P, Tomita T, Nakaya K, Lee V . Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol. 1998; 152(4):879-84. PMC: 1858234. View

15.

Steegmaier M, Hoffmann M, Baum A, Lenart P, Petronczki M, Krssak M . BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007; 17(4):316-22. DOI: 10.1016/j.cub.2006.12.037. View

16.

Anderson J, Walker D, Goldstein J, de Laat R, Banducci K, Caccavello R . Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem. 2006; 281(40):29739-52. DOI: 10.1074/jbc.M600933200. View

17.

Polymeropoulos M, Lavedan C, Leroy E, Ide S, Dehejia A, Dutra A . Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997; 276(5321):2045-7. DOI: 10.1126/science.276.5321.2045. View

18.

Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg M . alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002; 4(2):160-4. DOI: 10.1038/ncb748. View

19.

Johnson E, Stewart K, Woods K, Giranda V, Luo Y . Pharmacological and functional comparison of the polo-like kinase family: insight into inhibitor and substrate specificity. Biochemistry. 2007; 46(33):9551-63. DOI: 10.1021/bi7008745. View

20.

Singleton A, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J . alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003; 302(5646):841. DOI: 10.1126/science.1090278. View