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Cited by 265Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeurological disorders and treatments

Ribosomal Protein s15 Phosphorylation Mediates LRRK2 Neurodegeneration in Parkinson’s Disease

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Martin, Ian, Kim, Jungwoo Wren, Lee, Byoung Dae, Kang, Ho Chul, Xu, Jin-Chong, Jia, Hao, Stankowski, Jeannette, Kim, Min-Sik +9 more·2014·Cell
DOI 10.1016/j.cell.2014.01.064PMC PMC4040530
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Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson's disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo.

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  • Defects in mRNA translation are linked to autosomal dominant PD and autosomal recessive PD, where there is aberrant bulk protein synthesis coupled to neurodegeneration.

    “Defects in mRNA translation are linked to autosomal dominant PD (5,6) and autosomal recessive PD (7), where there is aberrant bulk protein synthesis that is coupled to neurodegeneration (8,9).”

    From Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis (2022) · cites this paper as [5]

  • This aberrant protein synthesis is in part mediated by dysregulation of LRRK2 phosphorylation of ribosomal proteins and PINK1 and parkin modulation of 4E-BP.

    “This aberrant protein synthesis is, in part, mediated by dysregulation of LRRK2 phosphorylation of ribosomal proteins (5,6) and PTEN-induced kinase 1 (PINK1) and parkin modulation of eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP) (7).”

    From Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis (2022) · cites this paper as [5]

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Research works printed but not linked: 38

  1. Anand VS Reichling LJ Lipinski K Stochaj W Duan W Kelleher K Pungaliya P Brown EL Reinhart PH Somberg R 2009 Investigation of leucine-rich repeat kinase 2: enzymological properties and novel assays FEBS J 276 466 478 19076219
  2. Belin S Hacot S Daudignon L Therizols G Pourpe S Mertani HC Rosa-Calatrava M Diaz JJ 2010 Purification of ribosomes from human cell lines Curr Protoc Cell Biol Chapter 3 Unit 3 40 21154551
  3. Chartier-Harlin MC Dachsel JC Vilarino-Guell C Lincoln SJ Lepretre F Hulihan MM Kachergus J Milnerwood AJ Tapia L Song MS 2011 Translation initiator EIF4G1 mutations in familial Parkinson disease Am J Hum Genet 89 398 406 21907011 PMC3169825
  4. Cookson MR 2010 The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease Nat Rev Neurosci 11 791 797 21088684 PMC4662256
  5. Covy JP Giasson BI 2009 Identification of compounds that inhibit the kinase activity of leucine-rich repeat kinase 2 Biochem Biophys Res Commun 378 473 477 19027715 PMC2633649
  6. Deng X Dzamko N Prescott A Davies P Liu Q Yang Q Lee JD Patricelli MP Nomanbhoy TK Alessi DR 2011 Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2 Nat Chem Biol 7 203 205 21378983 PMC3287420
  7. Deng X Dzamko N Prescott A Davies P Liu Q Yang Q Lee JD Patricelli MP Nomanbhoy TK Alessi DR 2011 Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2 Nature chemical biology 7 203 205 PMC3287420 21378983
  8. Gehrke S Imai Y Sokol N Lu B 2010 Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression Nature 466 637 641 20671708 PMC3049892
  9. Greggio E Jain S Kingsbury A Bandopadhyay R Lewis P Kaganovich A van der Brug MP Beilina A Blackinton J Thomas KJ 2006 Kinase activity is required for the toxic effects of mutant LRRK2/dardarin Neurobiol Dis 23 329 341 16750377
  10. Imai Y Gehrke S Wang HQ Takahashi R Hasegawa K Oota E Lu B 2008 Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila EMBO J 27 2432 2443 18701920 PMC2543051
  11. Khairulina J Graifer D Bulygin K Ven'yaminova A Frolova L Karpova G 2010 Eukaryote-specific motif of ribosomal protein S15 neighbors A site codon during elongation and termination of translation Biochimie 92 820 825 20206660
  12. Kumar A Greggio E Beilina A Kaganovich A Chan D Taymans JM Wolozin B Cookson MR 2010 The Parkinson's disease associated LRRK2 exhibits weaker in vitro phosphorylation of 4E-BP compared to autophosphorylation PLoS One 5 e8730 20090955 PMC2806920
  13. Lagier-Tourenne C Polymenidou M Hutt KR Vu AQ Baughn M Huelga SC Clutario KM Ling SC Liang TY Mazur C 2012 Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs Nat Neurosci 15 1488 1497 23023293 PMC3586380
  14. Lee BD Shin JH VanKampen J Petrucelli L West AB Ko HS Lee YI Maguire-Zeiss KA Bowers WJ Federoff HJ 2010 Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease Nat Med 16 998 1000 20729864 PMC2935926
  15. Li X Moore DJ Xiong Y Dawson TM Dawson VL 2010 Reevaluation of phosphorylation sites in the Parkinson disease-associated leucine-rich repeat kinase 2 J Biol Chem 285 29569 29576 20595391 PMC2937988
  16. Liu Z Wang X Yu Y Li X Wang T Jiang H Ren Q Jiao Y Sawa A Moran T 2008 A Drosophila model for LRRK2-linked parkinsonism Proc Natl Acad Sci U S A 105 2693 2698 18258746 PMC2268198
  17. Luzon-Toro B Rubio de la Torre E Delgado A Perez-Tur J Hilfiker S 2007 Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation Hum Mol Genet 16 2031 2039 17584768
  18. MacLeod D Dowman J Hammond R Leete T Inoue K Abeliovich A 2006 The familial Parkinsonism gene LRRK2 regulates neurite process morphology Neuron 52 587 593 17114044
  19. Martin I Dawson VL Dawson TM 2011 Recent advances in the genetics of Parkinson's disease Annu Rev Genomics Hum Genet 12 301 325 21639795 PMC4120236
  20. Matta S Van Kolen K da Cunha R van den Bogaart G Mandemakers W Miskiewicz K De Bock PJ Morais VA Vilain S Haddad D 2012 LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis Neuron 75 1008 1021 22998870
  21. Moreno JA Radford H Peretti D Steinert JR Verity N Martin MG Halliday M Morgan J Dinsdale D Ortori CA 2012 Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration Nature 485 507 511 22622579 PMC3378208
  22. Nuytemans K Bademci G Inchausti V Dressen A Kinnamon DD Mehta A Wang L Zuchner S Beecham GW Martin ER 2013 Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease Neurology 80 982 989 23408866 PMC3653206
  23. Paisan-Ruiz C Jain S Evans EW Gilks WP Simon J van der Brug M Lopez de Munain A Aparicio S Gil AM Khan N 2004 Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease Neuron 44 595 600 15541308
  24. Parisiadou L Xie C Cho HJ Lin X Gu XL Long CX Lobbestael E Baekelandt V Taymans JM Sun L 2009 Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis J Neurosci 29 13971 13980 19890007 PMC2807632
  25. Pisarev AV Kolupaeva VG Pisareva VP Merrick WC Hellen CU Pestova TV 2006 Specific functional interactions of nucleotides at key -3 and +4 positions flanking the initiation codon with components of the mammalian 48S translation initiation complex Genes Dev 20 624 636 16510876 PMC1410799
  26. Ramsden N Perrin J Ren Z Lee BD Zinn N Dawson VL Tam D Bova M Lang M Drewes G 2011 Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons ACS Chem Biol 6 1021 1028 21812418 PMC3688284
  27. Scheper GC van der Knaap MS Proud CG 2007 Translation matters: protein synthesis defects in inherited disease Nat Rev Genet 8 711 723 17680008
  28. Smith WW Pei Z Jiang H Dawson VL Dawson TM Ross CA 2006 Kinase activity of mutant LRRK2 mediates neuronal toxicity Nat Neurosci 9 1231 1233 16980962
  29. Sen S Webber PJ West AB 2009 Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization J Biol Chem 284 36346 36356 19826009 PMC2794750
  30. Smith WW Pei Z Jiang H Dawson VL Dawson TM Ross CA 2006 Kinase activity of mutant LRRK2 mediates neuronal toxicity Nature neuroscience 9 1231 1233 16980962
  31. Thoreen CC Chantranupong L Keys HR Wang T Gray NS Sabatini DM 2012 A unifying model for mTORC1-mediated regulation of mRNA translation Nature 485 109 113 22552098 PMC3347774
  32. Tollervey JR Curk T Rogelj B Briese M Cereda M Kayikci M Konig J Hortobagyi T Nishimura AL Zupunski V 2011 Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nat Neurosci 14 452 458 21358640 PMC3108889
  33. Trancikova A Mamais A Webber PJ Stafa K Tsika E Glauser L West AB Bandopadhyay R Moore DJ 2012 Phosphorylation of 4E-BP1 in the mammalian brain is not altered by LRRK2 expression or pathogenic mutations PLoS One 7 e47784 23082216 PMC3474772
  34. Tsika E Moore DJ 2012 Mechanisms of LRRK2-mediated neurodegeneration Curr Neurol Neurosci Rep 12 251 260 22441981
  35. Webber PJ Smith AD Sen S Renfrow MB Mobley JA West AB 2011 Autophosphorylation in the leucine-rich repeat kinase 2 (LRRK2) GTPase domain modifies kinase and GTP-binding activities J Mol Biol 412 94 110 21806997 PMC3158845
  36. West AB Moore DJ Choi C Andrabi SA Li X Dikeman D Biskup S Zhang Z Lim KL Dawson VL 2007 Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity Hum Mol Genet 16 223 232 17200152
  37. Xiong Y Coombes CE Kilaru A Li X Gitler AD Bowers WJ Dawson VL Dawson TM Moore DJ 2010 GTPase activity plays a key role in the pathobiology of LRRK2 PLoS Genet 6 e1000902 20386743 PMC2851569
  38. Zimprich A Biskup S Leitner P Lichtner P Farrer M Lincoln S Kachergus J Hulihan M Uitti RJ Calne DB 2004 Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology Neuron 44 601 607 15541309

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Authors
Martin, I., Kim, J. W., Lee, B. D., Kang, H. C., Xu, J.-C., Jia, H., Stankowski, J., Kim, M.-S., Zhong, J., Kumar, M., Andrabi, S. A., Xiong, Y., Dickson, D. W., Wszolek, Z. K., Pandey, A., Dawson, T. M., & Dawson, V. L.
Affiliations
  • Johns Hopkins University (US)
  • Mayo Clinic (US)
Corresponding author
  • Dawson, Ted M.
  • Dawson, Valina L.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2014-04
Volume
157
Issue
2
Pages
472-485
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2014.01.064
PMC
PMC4040530
OpenAlex
W2126238482
Cited by
265
References
3
Citations by year
2026: 11 · 2025: 18 · 2024: 11 · 2023: 26 · 2022: 13 · 2021: 20 · 2020: 29 · 2019: 21 · 2018: 26 · 2017: 23 · 2016: 27 · 2015: 26 · 2014: 14
FWCI
20.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • AJOU Open Repository (Ajou University) (submittedVersion)
Funders
National Institute of Neurological Disorders and Stroke (P50NS038377, P50NS072187)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
Keywords
LRRK2, Parkinson's disease, ribosomal protein S15, phosphorylation, dopaminergic neuron loss, mRNA translation, protein synthesis, neurodegeneration, Drosophila model
MeSH terms
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Amino Acid Sequence, Animals, Drosophila melanogaster, Humans, Molecular Sequence Data, Neurons, Parkinson Disease, Ribosomal Proteins, Protein Serine-Threonine Kinases

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