title: Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity.
abstract: BACKGROUND
  Recent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2) gene with Parkinson's disease (PD). Among the mutations, LRRK2 c.4883G>C (R1628P) variant was identified to have a significant association with the risk of PD in ethnic Han-Chinese populations. But the molecular pathological mechanisms of R1628P mutation in PD is still unknown.
  
  
  RESULTS
  Unlike other LRRK2 mutants in the Roc-COR-Kinase domain, the R1628P mutation didn't alter the LRRK2 kinase activity and promote neuronal death directly. LRRK2 R1628P mutation increased the binding affinity of LRRK2 with Cyclin-dependent kinase 5 (Cdk5). Interestingly, R1628P mutation turned its adjacent amino acid residue S1627 on LRRK2 protein to a novel phosphorylation site of Cdk5, which could be defined as a typical type II (+) phosphorylation-related single nucleotide polymorphism. Importantly, we showed that the phosphorylation of S1627 by Cdk5 could activate the LRRK2 kinase, and neurons ectopically expressing R1628P displayed a higher sensitivity to 1-methyl-4-phenylpyridinium, a bioactive metabolite of environmental toxin MPTP, in a Cdk5-dependent manner.
  
  
  CONCLUSIONS
  Our data indicate that Parkinson-related LRRK2 mutation R1628P leads to Cdk5 phosphorylation of LRRK2 at S1627, which would upregulate the kinase activity of LRRK2 and consequently cause neuronal death.
authors.affiliation: Department of Neurobiology, Tongji Medical School, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China.|Central laboratory, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, Jiangsu Province, 212000, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Wuhan Union hospital, Tongji Medical School, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province, 430022, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ming
authors.affiliation: Department of Neurobiology, Tongji Medical School, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China.|Key Laboratory of Neurological Diseases, Ministry of Education, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Tongji Medical School, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China.
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Tongji Medical School, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China.
authors.forename: Fengjuan
authors.initials: F
authors.lastname: Jiao
authors.affiliation: Department of Neurobiology, Tongji Medical School, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China.|Key Laboratory of Neurological Diseases, Ministry of Education, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tian
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D006540:Herbicides; D012694:Serine; D051360:Cyclin-Dependent Kinase 5; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D015655:1-Methyl-4-phenylpyridinium