LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration.

Zhili Gu,Guanghong Luo,Dong Wang,Wu Zhang,Kai Wang,Shu Yu,Ruili Feng,Xiao Cheng,Shiqing Zhang,Hai Huang,Tieqiao Wen,Jiang Xie,Meng Jiang,Ying Xia

doi:10.1038/srep12564

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.

Highlights

Parkinson’s disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra
To gain a global mapping of the target proteins induced by A30P/A53T, a 2-dimensional electrophoresis (2DE) approach was used to analyze protein expression differences at the proteomic level (S-Fig. 1)
In A30P or A53T mutants, we found that the presence of β -tub56D and Idh, (S-table 1 and S-table 2) which was further validated in two genotypes of Drosophilae (S-Fig. 2A–L). β -tub56D is one of the cytoskeletal proteins

Summary

Introduction

Parkinson’s disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra. 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 Ser[129] phosphorylation by identification of LK6 knockout and overexpression. Parkinson’s disease (PD) is a common age-associated neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and the accumulation of protein aceousintraneuronal inclusions known as Lewy bodies Karuppagounder, Brahmachari[1,2]. AsLK6 is homologue of human Mnk2a, we further identified that Mnk2a can phosphorylate α -synuclein by the ERK signal pathway, and leads to α -synuclein inclusion (Lewy body) agglomeration in human and mouse neurons, showing that Mnk2a may play a pivotal role in the formation of Parkinson’s disease

Objectives

Methods

Results

Conclusion