title: LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration.
abstract: Parkinson's disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra. Alpha-synuclein phosphorylation and α-synuclein inclusion (Lewy body) become a main contributor, but little is known about their formation mechanism. Here we used protein expression profiling of PD to construct a model of their signalling network from drsophila to human and nominate major nodes that regulate PD development. We found in this network that LK6, a serine/threonine protein kinase, plays a key role in promoting α-synuclein Ser129 phosphorylation by identification of LK6 knockout and overexpression. In vivo test was further confirmed that LK6 indeed enhances α-synuclein phosphorylation, accelerates the death of dopaminergic neurons, reduces the climbing ability and shortens the the life span of drosophila. Further, MAP kinase-interacting kinase 2a (Mnk2a), a human homolog of LK6, also been shown to make α-synuclein phosphorylation and leads to α-synuclein inclusion formation. On the mechanism, the phosphorylation mediated by LK6 and Mnk2a is controlled through ERK signal pathway by phorbolmyristate acetate (PMA) avtivation and PD98059 inhibition. Our findings establish pivotal role of Lk6 and Mnk2a in unprecedented signalling networks, may lead to new therapies preventing α-synuclein inclusion formation and neurodegeneration.
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.|Institute of systems biology, Shanghai University, 99 Shang Da Road, 200444, Shanghai.
authors.forename: Shiqing
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School of computer engineering and science, Shanghai University, Nanchen Road, 200444, Shanghai.
authors.forename: Jiang
authors.initials: J
authors.lastname: Xie
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.
authors.forename: Shu
authors.initials: S
authors.lastname: Yu
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.
authors.forename: Ruili
authors.initials: R
authors.lastname: Feng
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Luo
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.|Institute of systems biology, Shanghai University, 99 Shang Da Road, 200444, Shanghai.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.
authors.forename: Meng
authors.initials: M
authors.lastname: Jiang
authors.affiliation: School of computer engineering and science, Shanghai University, Nanchen Road, 200444, Shanghai.
authors.forename: Xiao
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: School of computer engineering and science, Shanghai University, Nanchen Road, 200444, Shanghai.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, 200444, Shanghai.|Institute of systems biology, Shanghai University, 99 Shang Da Road, 200444, Shanghai.
authors.forename: Tieqiao
authors.initials: T
authors.lastname: Wen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D005260:Female; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology*; D010770:Phosphotransferases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D051844:alpha-Synuclein; D010770:Phosphotransferases; C500415:Lk6 protein, Drosophila; D020929:Mitogen-Activated Protein Kinase Kinases