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Cited by 56Parkinson's Disease Mechanisms and TreatmentsRNA and protein synthesis mechanismsNuclear Receptors and Signaling

Defects in mRNA Translation in LRRK2-Mutant hiPSC-Derived Dopaminergic Neurons Lead to Dysregulated Calcium Homeostasis

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Kim, Jungwoo Wren, Yin, Xiling, Jhaldiyal, Aanishaa, Khan, Mohammed Repon, Martin, Ian, Xie, Zhong, Perez-Rosello, Tamara, Kumar, Manoj +8 more·2020·Cell Stem Cell
DOI 10.1016/j.stem.2020.08.002PMC PMC7542555
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Abstract

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familial Parkinson's disease (PD). This mutation results in dopaminergic neurodegeneration via dysregulated protein translation, although how alterations in protein synthesis contribute to neurodegeneration in human neurons is not known. Here we define the translational landscape in LRRK2-mutant dopaminergic neurons derived from human induced pluripotent stem cells (hiPSCs) via ribosome profiling. We found that mRNAs that have complex secondary structure in the 5' untranslated region (UTR) are translated more efficiently in G2019S LRRK2 neurons. This leads to the enhanced translation of multiple genes involved in Ca 2+ regulation and to increased Ca 2+ influx and elevated intracellular Ca 2+ levels, a major contributor to PD pathogenesis. This study reveals a link between dysregulated translation control and Ca 2+ homeostasis in G2019S LRRK2 human dopamine neurons, which potentially contributes to the progressive and selective dopaminergic neurotoxicity in PD.

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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 [6]

    The Introduction (page not available in our copy) links dominant LRRK2-mutant PD to dysregulated translation and reports increased global protein synthesis coupled to neurotoxicity in Drosophila models. The paper does not establish the corresponding claim for autosomal recessive PD; its human-neuron findings concern altered translation of particular mRNAs rather than a demonstrated change in bulk protein synthesis. (LLM, conf=0.86)

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  • 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 [6]

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Research works printed but not linked: 61

  1. Abeliovich A, and Gitler AD (2016). Defects in trafficking bridge Parkinson's disease pathology and genetics. Nature 539, 207– 216. 27830778
  2. Anger AM, Armache JP, Berninghausen O, Habeck M, Subklewe M, Wilson DN, and Beckmann R (2013). Structures of the human and Drosophila 80S ribosome. Nature 497, 80– 85. 23636399
  3. Bhaskar V, Graff-Meyer A, Schenk AD, Cavadini S, von Loeffelholz O, Natchiar SK, Artus-Revel CG, Hotz HR, Bretones G, Klaholz BP, (2020). Dynamics of uS19 C-Terminal Tail during the Translation Elongation Cycle in Human Ribosomes. Cell Rep 31, 107473. 32268098
  4. Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pages F, Trajanoski Z, and Galon J (2009). ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25, 1091– 1093. 19237447 PMC2666812
  5. Bretones G, Álvarez MG, Arango JR, Rodríguez D, Nadeu F, Prado MA, Valdés-Mas R, Puente DA, Paulo JA, Delgado J, (2018). Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia. Blood 132, 2375– 2388. 30181176 PMC6410914
  6. Cherra SJ 3rd, Steer E, Gusdon AM, Kiselyov K, and Chu CT (2013). Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol 182, 474– 484. 23231918 PMC3562730
  7. Cookson MR (2010). The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci 11, 791– 797. 21088684 PMC4662256
  8. Cookson MR (2016). Cellular functions of LRRK2 implicate vesicular trafficking pathways in Parkinson's disease. Biochem Soc Trans 44, 1603– 1610. 27913668
  9. Dalal JS, Yang C, Sapkota D, Lake AM, O'Brien DR, and Dougherty JD (2017). Quantitative Nucleotide Level Analysis of Regulation of Translation in Response to Depolarization of Cultured Neural Cells. Front Mol Neurosci 10, 9. 28190998 PMC5269599
  10. Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR, Klein C, Vila M, and Bezard E (2013). Lysosomal impairment in Parkinson's disease. Mov Disord 28, 725– 732. 23580333 PMC5131721
  11. 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
  12. Dolmetsch RE, Pajvani U, Fife K, Spotts JM, and Greenberg ME (2001). Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294, 333– 339. 11598293
  13. Dominy JE, and Puigserver P (2013). Mitochondrial biogenesis through activation of nuclear signaling proteins. Cold Spring Harb Perspect Biol 5. PMC3685894 23818499
  14. Ebert DH, and Greenberg ME (2013). Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327– 337. 23325215 PMC3576027
  15. Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, Kowa H, Tsuji S, and Obata F (2005). An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol 57, 918– 921. 15880653
  16. Gehrke S, Imai Y, Sokol N, and Lu B (2010). Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466, 637– 641. 20671708 PMC3049892
  17. Gomez-Suaga P, Luzon-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, and Hilfiker S (2012). Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet 21, 511– 525. 22012985 PMC3259011
  18. 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
  19. Hinnebusch AG, Ivanov IP, and Sonenberg N (2016). Translational control by 5'-untranslated regions of eukaryotic mRNAs. Science 352, 1413– 1416. 27313038 PMC7422601
  20. Hoyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, Bianchi K, Fehrenbacher N, Elling F, Rizzuto R, (2007). Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 25, 193– 205. 17244528
  21. Imai Y, Gehrke S, Wang HQ, Takahashi R, Hasegawa K, Oota E, and Lu B (2008). Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J 27, 2432– 2443. 18701920 PMC2543051
  22. Ingolia NT, Brar GA, Rouskin S, McGeachy AM, and Weissman JS (2012). The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments. Nat Protoc 7, 1534– 1550. 22836135 PMC3535016
  23. Ingolia NT, Ghaemmaghami S, Newman JR, and Weissman JS (2009). Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218– 223. 19213877 PMC2746483
  24. Khairulina J, Graifer D, Bulygin K, Ven'yaminova A, Frolova L, and 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
  25. Khatter H, Myasnikov AG, Natchiar SK, and Klaholz BP (2015). Structure of the human 80S ribosome. Nature 520, 640– 645. 25901680
  26. Korecka JA, Talbot S, Osborn TM, de Leeuw SM, Levy SA, Ferrari EJ, Moskites A, Atkinson E, Jodelka FM, Hinrich AJ, (2019). Neurite Collapse and Altered ER Ca. Stem Cell Reports 12, 29– 41. 30595548 PMC6335600
  27. Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, (2011). Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480, 547– 551. 22056989 PMC3245796
  28. Langmead B, and Salzberg SL (2012). Fast gapped-read alignment with Bowtie 2. Nat Methods 9, 357– 359. 22388286 PMC3322381
  29. Lawrence M, Huber W, Pages H, Aboyoun P, Carlson M, Gentleman R, Morgan MT, and Carey VJ (2013). Software for computing and annotating genomic ranges. PLoS Comput Biol 9, e1003118. 23950696 PMC3738458
  30. Lomakin IB, and Steitz TA (2013). The initiation of mammalian protein synthesis and mRNA scanning mechanism. Nature 500, 307– 311. 23873042 PMC3748252
  31. Lorenz R, Bernhart SH, Honer Zu Siederdissen C, Tafer H, Flamm C, Stadler PF, and Hofacker IL (2011). ViennaRNA Package 2.0. Algorithms Mol Biol 6, 26. 22115189 PMC3319429
  32. Love MI, Huber W, and Anders S (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15, 550. 25516281 PMC4302049
  33. Luzon-Toro B, Rubio de la Torre E, Delgado A, Perez-Tur J, and 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
  34. MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, and Abeliovich A (2006). The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52, 587– 593. 17114044
  35. Martin I, Kim JW, Dawson VL, and Dawson TM (2014a). LRRK2 pathobiology in Parkinson's disease. J Neurochem 131, 554– 565. 25251388 PMC4237709
  36. Martin I, Kim JW, Lee BD, Kang HC, Xu JC, Jia H, Stankowski J, Kim MS, Zhong J, Kumar M, (2014b). Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157, 472– 485. 24725412 PMC4040530
  37. McGlincy NJ, and Ingolia NT (2017). Transcriptome-wide measurement of translation by ribosome profiling. Methods 126, 112– 129. 28579404 PMC5582988
  38. Mi H, Muruganujan A, Huang X, Ebert D, Mills C, Guo X, and Thomas PD (2019). Protocol Update for large-scale genome and gene function analysis with the PANTHER classification system (v.14.0). Nat Protoc 14, 703– 721. 30804569 PMC6519457
  39. Nicholls DG (2008). Oxidative stress and energy crises in neuronal dysfunction. Ann N Y Acad Sci 1147, 53– 60. 19076430
  40. Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig LS, Dauer W, Consiglio A, (2013). Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 16, 394– 406. 23455607 PMC3609872
  41. Pacelli C, Giguere N, Bourque MJ, Levesque M, Slack RS, and Trudeau LE (2015). Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons. Curr Biol 25, 2349– 2360. 26320949
  42. 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
  43. Penney J, Tsurudome K, Liao EH, Kauwe G, Gray L, Yanagiya A, M RC, Sonenberg N, and Haghighi AP (2016). LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction. Nat Commun 7, 12188. 27432119 PMC4960312
  44. Perier C, and Vila M (2012). Mitochondrial biology and Parkinson's disease. Cold Spring Harb Perspect Med 2, a009332. 22355801 PMC3281591
  45. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, and Ferrin TE (2004). UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 25, 1605– 1612. 15264254
  46. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, and Lang AE (2017). Parkinson disease. Nat Rev Dis Primers 3, 17013. 28332488
  47. 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
  48. Reinecke F, Smeitink JA, and van der Westhuizen FH (2009). OXPHOS gene expression and control in mitochondrial disorders. Biochim Biophys Acta 1792, 1113– 1121. 19389473
  49. Reinhardt P, Schmid B, Burbulla LF, Schondorf DC, Wagner L, Glatza M, Hoing S, Hargus G, Heck SA, Dhingra A, (2013). Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12, 354– 367. 23472874
  50. Schwab AJ, and Ebert AD (2015). Neurite Aggregation and Calcium Dysfunction in iPSC-Derived Sensory Neurons with Parkinson's Disease-Related LRRK2 G2019S Mutation. Stem Cell Reports 5, 1039– 1052. 26651604 PMC4682343
  51. Sharifulin DE, Grosheva AS, Bartuli YS, Malygin AA, Meschaninova MI, Ven'yaminova AG, Stahl J, Graifer DM, and Karpova GG (2015). Molecular contacts of ribose-phosphate backbone of mRNA with human ribosome. Biochim Biophys Acta 1849, 930– 939. 26066980
  52. Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, and Ross CA (2006). Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 9, 1231– 1233. 16980962
  53. Surmeier DJ, Guzman JN, Sanchez J, and Schumacker PT (2012). Physiological phenotype and vulnerability in Parkinson's disease. Cold Spring Harb Perspect Med 2, a009290. 22762023 PMC3385938
  54. Surmeier DJ, Schumacker PT, Guzman JD, Ilijic E, Yang B, and Zampese E (2017). Calcium and Parkinson's disease. Biochem Biophys Res Commun 483, 1013– 1019. 27590583 PMC5449761
  55. Trapnell C, Pachter L, and Salzberg SL (2009). TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105– 1111. 19289445 PMC2672628
  56. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, and Dawson TM (2005). Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 102, 16842– 16847. 16269541 PMC1283829
  57. 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
  58. Xiang G, Pan L, Xing W, Zhang L, Huang L, Yu J, Zhang R, Wu J, Cheng J, and Zhou Y (2007). Identification of activity-dependent gene expression profiles reveals specific subsets of genes induced by different routes of Ca(2+) entry in cultured rat cortical neurons. J Cell Physiol 212, 126– 136. 17443680
  59. Xu JC, Fan J, Wang X, Eacker SM, Kam TI, Chen L, Yin X, Zhu J, Chi Z, Jiang H, (2016). Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. Sci Transl Med 8, 333ra348. PMC5595216 27053772
  60. Yap EL, and Greenberg ME (2018). Activity-Regulated Transcription: Bridging the Gap between Neural Activity and Behavior. Neuron 100, 330– 348. 30359600 PMC6223657
  61. 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
Kim, J. W., Yin, X., Jhaldiyal, A., Khan, M. R., Martin, I., Xie, Z., Perez-Rosello, T., Kumar, M., Abalde-Atristain, L., Xu, J., Chen, L., Eacker, S. M., Surmeier, D. J., Ingolia, N. T., Dawson, T. M., & Dawson, V. L.
Affiliations
  • Johns Hopkins University (US)
  • Northwestern University (US)
  • University of California, Berkeley (US)
Corresponding author
  • Dawson, Ted M.
  • Dawson, Valina L.
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2020-10
Volume
27
Issue
4
Pages
633-645.e7
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2020.08.002
PMC
PMC7542555
OpenAlex
W3081421442
Cited by
56
References
2
Citations by year
2026: 4 · 2025: 8 · 2024: 10 · 2023: 10 · 2022: 11 · 2021: 12 · 2020: 1
FWCI
3.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
LRRK2 G2019S mutation, Parkinson's disease, dopaminergic neurons, mRNA translation, ribosome profiling, calcium homeostasis, calcium influx, translational regulation, induced pluripotent stem cells, neurodegeneration
MeSH terms
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Calcium, Homeostasis, Humans, Mutation, Parkinson Disease, Protein Biosynthesis, Induced Pluripotent Stem Cells, Dopaminergic Neurons

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