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Overexpression of Parkin in the Neuronal Progenitor Cells from a Patient with Parkinson’s Disease Shifts the Transcriptome Towards the Normal State

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Abstract

Parkinson’s disease (PD) is a neurodegenerative pathology caused by the progressive loss of dopaminergic neurons in the substantia nigra. Juvenile PD is known to be strongly associated with mutations in the PARK2 gene encoding E3 ubiquitin ligase Parkin. Despite numerous studies, molecular mechanisms that trigger PD remain largely unknown. Here, we compared the transcriptome of the neural progenitor (NP) cell line, derived from a PD patient with PARK2 mutation resulting in Parkin loss, with the transcriptome of the same NPs but expressing transgenic Parkin. We found that Parkin overexpression led to the substantial recovery of the transcriptome of NPs to a normal state indicating that alterations of transcription in PD-derived NPs were mainly caused by PARK2 mutations. Among genes significantly dysregulated in PD-derived NPs, 106 genes unambiguously restored their expression after reestablishing of the Parkin level. Based on the selected gene sets, we revealed the enriched Gene Ontology (GO) pathways including signaling, neurotransmitter transport and metabolism, response to stimulus, and apoptosis. Strikingly, dopamine receptor D4 that was previously associated with PD appears to be involved in the maximal number of GO-enriched pathways and therefore may be considered as a potential trigger of PD progression. Our findings may help in the screening for promising targets for PD treatment.

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Data Availability

The datasets generated during and analyzed during the current study are available in the Gene Expression Omnibus (GEO) repository under accession number GSE205235 (direct URL to data: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE205235).

References

  1. Lynch-Day MA, Mao K, Wang K, Zhao M, Klionsky DJ (2012) The role of autophagy in Parkinson’s disease. Cold Spring Harb Perspect Med 2(4):a009357. https://doi.org/10.1101/cshperspect.a009357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Oosterveen T, Garção P, Moles-Garcia E, Soleilhavoup C, Travaglio M, Sheraz S, Peltrini R, Patrick K et al (2021) Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson’s disease. Stem Cell Reports 16(11):2718–2735. https://doi.org/10.1016/j.stemcr.2021.09.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Coppedè F (2012) Genetics and epigenetics of Parkinson’s disease. SciWorldJ 2012:489830. https://doi.org/10.1100/2012/489830

    Article  CAS  Google Scholar 

  4. Chu YT, Tai CH, Lin CH, Wu RM (2021) Updates on the genetics of Parkinson’s disease: clinical implications and future treatment. Acta Neurol Taiwan 30(3):83–93

    Google Scholar 

  5. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608. https://doi.org/10.1038/33416

    Article  CAS  PubMed  Google Scholar 

  6. Wang XL, Feng ST, Wang ZZ, Yuan YH, Chen NH, Zhang Y (2021) Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control in Parkinson’s disease. Cell Mol Neurobiol 41(7):1395–1411. https://doi.org/10.1007/s10571-020-00914-2

    Article  CAS  PubMed  Google Scholar 

  7. Kamienieva I, Duszyński J, Szczepanowska J (2021) Multitasking guardian of mitochondrial quality: Parkin function and Parkinson’s disease. Transl Neurodegener 10(1):5. https://doi.org/10.1186/s40035-020-00229-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Joch M, Ase AR, Chen CX, MacDonald PA, Kontogiannea M, Corera AT, Brice A, Séguéla P et al (2007) Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels. Mol Biol Cell 18(8):3105–3118. https://doi.org/10.1091/mbc.e05-11-1027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kumar A, Aguirre JD, Condos TE, Martinez-Torres RJ, Chaugule VK, Toth R, Sundaramoorthy R, Mercier P et al (2015) Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis. EMBO J 34(20):2506–2521. https://doi.org/10.15252/embj.201592337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Moskal N, Riccio V, Bashkurov M, Taddese R, Datti A, Lewis PN, Angus McQuibban G (2020) ROCK inhibitors upregulate the neuroprotective Parkin-mediated mitophagy pathway. Nat Commun 11(1):88. https://doi.org/10.1038/s41467-019-13781-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kramer ER (2015) The neuroprotective and regenerative potential of parkin and GDNF/Ret signaling in the midbrain dopaminergic system. Neural Regen Res 10(11):1752–1753. https://doi.org/10.4103/1673-5374.165295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cakir Z, Funk K, Lauterwasser J, Todt F, Zerbes RM, Oelgeklaus A, Tanaka A, van der Laan M et al (2017) Parkin promotes proteasomal degradation of misregulated BAX. J Cell Sci 130(17):2903–2913. https://doi.org/10.1242/jcs.200162

    Article  CAS  PubMed  Google Scholar 

  13. Zhang X, Lin C, Song J, Chen H, Chen X, Ren L, Zhou Z, Pan J et al (2019) Parkin facilitates proteasome inhibitor-induced apoptosis via suppression of NF-κB activity in hepatocellular carcinoma. Cell Death Dis 10(10):719. https://doi.org/10.1038/s41419-019-1881-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yoshii SR, Kishi C, Ishihara N, Mizushima N (2011) Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem 286(22):19630–19640. https://doi.org/10.1074/jbc.M110.209338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191(7):1367–1380. https://doi.org/10.1083/jcb.201007013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bendikov-Bar I, Rapaport D, Larisch S, Horowitz M (2014) Parkin-mediated ubiquitination of mutant glucocerebrosidase leads to competition with its substrates PARIS and ARTS. Orphanet J Rare Dis 9:86. https://doi.org/10.1186/1750-1172-9-86

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kemeny S, Dery D, Loboda Y, Rovner M, Lev T, Zuri D, Finberg JP, Larisch S (2012) Parkin promotes degradation of the mitochondrial pro-apoptotic ARTS protein. PLoS One 7(7):e38837. https://doi.org/10.1371/journal.pone.0038837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Khandelwal PJ, Moussa CE (2010) The relationship between Parkin and protein aggregation in neurodegenerative diseases. Front Psychiatry 1:15. https://doi.org/10.3389/fpsyt.2010.00015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yasuda T, Miyachi S, Kitagawa R, Wada K, Nihira T, Ren YR, Hirai Y, Ageyama N et al (2007) Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates. Neuroscience 144(2):743–753. https://doi.org/10.1016/j.neuroscience.2006.09.052

    Article  CAS  PubMed  Google Scholar 

  20. Chung E, Choi Y, Park J, Nah W, Park J, Jung Y, Lee J, Lee H et al (2020) Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein. Sci Adv 6(18):eaba1193. https://doi.org/10.1126/sciadv.aba1193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chopra R, Kalaiarasan P, Ali S, Srivastava AK, Aggarwal S, Garg VK, Bhattacharya SN, Bamezai RN (2014) PARK2 and proinflammatory/anti-inflammatory cytokine gene interactions contribute to the susceptibility to leprosy: a case-control study of North Indian population. BMJ Open 4(2):e004239. https://doi.org/10.1136/bmjopen-2013-004239

    Article  PubMed  PubMed Central  Google Scholar 

  22. Henn IH, Bouman L, Schlehe JS, Schlierf A, Schramm JE, Wegener E, Nakaso K, Culmsee C et al (2007) Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling. J Neurosci 27(8):1868–1878. https://doi.org/10.1523/JNEUROSCI.5537-06.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sha D, Chin LS, Li L (2010) Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum Mol Genet 19(2):352–363. https://doi.org/10.1093/hmg/ddp501

    Article  CAS  PubMed  Google Scholar 

  24. Frank-Cannon TC, Tran T, Ruhn KA, Martinez TN, Hong J, Marvin M, Hartley M, Treviño I et al (2008) Parkin deficiency increases vulnerability to inflammation-related nigral degeneration. J Neurosci 28(43):10825–10834. https://doi.org/10.1523/JNEUROSCI.3001-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Connor-Robson N, Booth H, Martin JG, Gao B, Li K, Doig N, Vowles J, Browne C et al (2019) An integrated transcriptomics and proteomics analysis reveals functional endocytic dysregulation caused by mutations in LRRK2. Neurobiol Dis 127:512–526. https://doi.org/10.1016/j.nbd.2019.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zambon F, Cherubini M, Fernandes HJR, Lang C, Ryan BJ, Volpato V, Bengoa-Vergniory N, Vingill S et al (2019) Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson’s iPSC-derived dopamine neurons. Hum Mol Genet 28(12):2001–2013. https://doi.org/10.1093/hmg/ddz038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chang KH, Huang CY, Ou-Yang CH, Ho CH, Lin HY, Hsu CL, Chen YT, Chou YC et al (2021) In vitro genome editing rescues parkinsonism phenotypes in induced pluripotent stem cells-derived dopaminergic neurons carrying LRRK2 p.G2019S mutation. Stem Cell Res Ther 12(1):508. https://doi.org/10.1186/s13287-021-02585-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Okarmus J, Havelund JF, Ryding M, Schmidt SI, Bogetofte H, Heon-Roberts R, Wade-Martins R, Cowley SA et al (2021) Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: altered mitochondrial and energy metabolism. Stem Cell Rep 16(6):1510–1526. https://doi.org/10.1016/j.stemcr.2021.04.022

    Article  CAS  Google Scholar 

  29. Kumar M, Acevedo-Cintrón J, Jhaldiyal A, Wang H, Andrabi SA, Eacker S, Karuppagounder SS, Brahmachari S et al (2020) Defects in mitochondrial biogenesis drive mitochondrial alterations in PARKIN-deficient human dopamine neurons. Stem Cell Rep 15(3):629–645. https://doi.org/10.1016/j.stemcr.2020.07.013

    Article  CAS  Google Scholar 

  30. Kuzumaki N, Suda Y, Iwasawa C, Narita M, Sone T, Watanabe M, Maekawa A, Matsumoto T et al (2019) Cell-specific overexpression of COMT in dopaminergic neurons of Parkinson’s disease. Brain 142(6):1675–1689. https://doi.org/10.1093/brain/awz084

    Article  PubMed  Google Scholar 

  31. Bogetofte H, Jensen P, Ryding M, Schmidt SI, Okarmus J, Ritter L, Worm CS, Hohnholt MC et al (2019) PARK2 mutation causes metabolic disturbances and impaired survival of human iPSC-derived neurons. Front Cell Neurosci 13:297. https://doi.org/10.3389/fncel.2019.00297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chung SY, Kishinevsky S, Mazzulli JR, Graziotto J, Mrejeru A, Mosharov EV, Puspita L, Valiulahi P et al (2016) Parkin and PINK1 patient iPSC-derived midbrain dopamine neurons exhibit mitochondrial dysfunction and α-synuclein accumulation. Stem Cell Rep 7(4):664–677. https://doi.org/10.1016/j.stemcr.2016.08.012

    Article  CAS  Google Scholar 

  33. Aboud AA, Tidball AM, Kumar KK, Neely MD, Han B, Ess KC, Hong CC, Erikson KM et al (2015) PARK2 patient neuroprogenitors show increased mitochondrial sensitivity to copper. Neurobiol Dis 73:204–212. https://doi.org/10.1016/j.nbd.2014.10.002

    Article  CAS  PubMed  Google Scholar 

  34. Vlasov IN, Alieva AK, Novosadova EV, Arsenyeva EL, Rosinskaya AV, Partevian SA, Grivennikov IA, Shadrina MI (2021) Transcriptome analysis of induced pluripotent stem cells and neuronal progenitor cells, derived from discordant monozygotic twins with Parkinson’s disease. Cells 10(12):3478. https://doi.org/10.3390/cells10123478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Novosadova EV, Nenasheva VV, Makarova IV, Dolotov OV, Inozemtseva LS, Arsenyeva EL, Chernyshenko SV, Sultanov RI et al (2020) Parkinson’s disease-associated changes in the expression of neurotrophic factors and their receptors upon neuronal differentiation of human induced pluripotent stem cells. J Mol Neurosci 70(4):514–521. https://doi.org/10.1007/s12031-019-01450-5

    Article  CAS  PubMed  Google Scholar 

  36. Nekrasov ED, Lebedeva OS, Chestkov IV, Syusina MA, Fedotova EYu, Lagarkova MA, Kiselev SL, Grivennikov IA et al (2011) Obtaining and characteristics of human induced pluripotent stem cells from skin fibroblasts of patients with neurodegenerative diseases. Cell Transplant Tissue Eng 6(4):82–88

    Google Scholar 

  37. Holmqvist S, Lehtonen S, Chumarina M, Puttonen KA, Azevedo C, Lebedeva O, Ruponen M, Oksanen M et al (2016) Creation of a library of induced pluripotent stem cells from Parkinsonian patients. NPJ Parkinsons Dis 2:16009. https://doi.org/10.1038/npjparkd.2016.9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Novosadova EV, Nekrasov ED, Chestkov IV, Surdina AV, Vasina AM, Bogomazova AN, Manuilova ES, Arsenyeva EL et al (2016) A platform for studying molecular and cellular mechanisms of Parkinson’s disease based on human induced pluripotent stem cells. Sovremennye Tehnologii v Med 8:157–166. https://doi.org/10.17691/stm2016.8.4.20

    Article  Google Scholar 

  39. Nekrasov ED, Vigont VA, Klyushnikov SA, Lebedeva OS, Vassina EM, Bogomazova AN, Chestkov IV, Semashko TA et al (2016) Manifestation of Huntington’s disease pathology in human induced pluripotent stem cell-derived neurons. Mol Neurodegener 11:27. https://doi.org/10.1186/s13024-016-0092-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lebedeva OS, Novosadova EV, Manuilova ES, Arsenyeva EL, Kiselev SL, Lagarkova MA, Khaspekov LG, Illarioshkin SN, Grivennikov IA (2014) Generation and characterization of a cellular model of Parkinson’s disease based on induced pluripotent stem cells. In: Tkachuk VA (ed.) Stem cells and regenerative medicine. MAKS press, Moscow

  41. Novosadova E, Anufrieva K, Kazantseva E, Arsenyeva E, Fedoseyeva V, Stepanenko E, Poberezhniy D, Illarioshkin S et al (2022) Transcriptome datasets of neural progenitors and neurons differentiated from induced pluripotent stem cells of healthy donors and Parkinson’s disease patients with mutations in the PARK2 gene. Data Brief 41:107958. https://doi.org/10.1016/j.dib.2022.107958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shuvalova LD, Eremeev AV, Bogomazova AN, Novosadova EV, Zerkalenkova EA, Olshanskaya YV, Fedotova EY, Glagoleva ES et al (2020) Generation of induced pluripotent stem cell line RCPCMi004-A derived from patient with Parkinson’s disease with deletion of the exon 2 in PARK2 gene. Stem Cell Res 44:101733. https://doi.org/10.1016/j.scr.2020.101733

    Article  CAS  PubMed  Google Scholar 

  43. Walker JM (1994) The bicinchoninic acid (BCA) assay for protein quantitation. Methods Mol Biol 32:5–8. https://doi.org/10.1385/0-89603-268-X:5

    Article  CAS  PubMed  Google Scholar 

  44. Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30(15):2114–2120. https://doi.org/10.1093/bioinformatics/btu170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C (2017) Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods 14(4):417–419. https://doi.org/10.1038/nmeth.4197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Soneson C, Love MI, Robinson MD (2015) Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Res 4:1521. https://doi.org/10.12688/f1000research.7563.2

    Article  PubMed  Google Scholar 

  47. Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15(12):550. https://doi.org/10.1186/s13059-014-0550-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. R Core Team (2021) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/

  49. Wickham H (2016) ggplot2: elegant graphics for data analysis. Springer-Verlag, New York

    Book  Google Scholar 

  50. Kolde R (2019) pheatmap: pretty heatmaps. R package version 1.0.12. https://CRAN.R-project.org/package=pheatmap

  51. Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, Vilo J (2019) g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res 47(W1):W191–W198. https://doi.org/10.1093/nar/gkz369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Supek F, Bošnjak M, Škunca N, Šmuc T (2011) REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS One 6(7):e21800. https://doi.org/10.1371/journal.pone.0021800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498–2504. https://doi.org/10.1101/gr.1239303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Schulte C, Gasser T (2011) Genetic basis of Parkinson’s disease: inheritance, penetrance, and expression. Appl Clin Genet 4:67–80. https://doi.org/10.2147/TACG.S11639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gil-Prieto R, Pascual-Garcia R, San-Roman-Montero J, Martinez-Martin P, Castrodeza-Sanz J, Gil-de-Miguel A (2016) Measuring the burden of hospitalization in patients with Parkinson’s disease in Spain. PLoS One 11(3):e0151563. https://doi.org/10.1371/journal.pone.0151563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Xu K, Alnaji N, Zhao J, Bertoni JM, Chen LW, Bhatti D, Qu M (2018) Comorbid conditions in Parkinson’s disease: a population-based study of statewide Parkinson’s disease registry. Neuroepidemiology 50(1–2):7–17. https://doi.org/10.1159/000484410

    Article  PubMed  Google Scholar 

  57. Koyano F, Yamano K, Kosako H, Tanaka K, Matsuda N (2019) Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL. J Biol Chem 294(26):10300–10314. https://doi.org/10.1074/jbc.RA118.006302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Xing S, Pan N, Xu W, Zhang J, Li J, Dang C, Liu G, Pei Z et al (2019) EphrinB2 activation enhances angiogenesis, reduces amyloid-β deposits and secondary damage in thalamus at the early stage after cortical infarction in hypertensive rats. J Cereb Blood Flow Metab 39(9):1776–1789. https://doi.org/10.1177/0271678X18769188

    Article  CAS  PubMed  Google Scholar 

  59. Zhong S, Pei D, Shi L, Cui Y, Hong Z (2019) Ephrin-B2 inhibits Aβ25-35-induced apoptosis by alleviating endoplasmic reticulum stress and promoting autophagy in HT22 cells. Neurosci Lett 704:50–56. https://doi.org/10.1016/j.neulet.2019.03.028

    Article  CAS  PubMed  Google Scholar 

  60. Islam F, Gopalan V, Lam AK (2018) RETREG1 (FAM134B): a new player in human diseases: 15 years after the discovery in cancer. J Cell Physiol 233(6):4479–4489. https://doi.org/10.1002/jcp.26384

    Article  CAS  PubMed  Google Scholar 

  61. Prevot TD, Sumitomo A, Tomoda T, Knutson DE, Li G, Mondal P, Banasr M, Cook JM et al (2021) Reversal of age-related neuronal atrophy by α5-GABAA receptor positive allosteric modulation. Cereb Cortex 31(2):1395–1408. https://doi.org/10.1093/cercor/bhaa310

    Article  PubMed  Google Scholar 

  62. Hokama M, Oka S, Leon J, Ninomiya T, Honda H, Sasaki K, Iwaki T, Ohara T et al (2014) Altered expression of diabetes-related genes in Alzheimer’s disease brains: the Hisayama study. Cereb Cortex 24(9):2476–2488. https://doi.org/10.1093/cercor/bht101

    Article  PubMed  Google Scholar 

  63. Qin L, Shu L, Zhong J, Pan H, Guo J, Sun Q, Yan X, Tang B et al (2019) Association of HIF1A and Parkinson’s disease in a Han Chinese population demonstrated by molecular inversion probe analysis. Neurol Sci 40(9):1927–1931. https://doi.org/10.1007/s10072-019-03905-4

    Article  PubMed  Google Scholar 

  64. Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E (2002) Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem 277(31):27975–27981. https://doi.org/10.1074/jbc.M204152200

    Article  CAS  PubMed  Google Scholar 

  65. Liu J, Zhang C, Zhao Y, Yue X, Wu H, Huang S, Chen J, Tomsky K et al (2017) Parkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression. Nat Commun 8(1):1823. https://doi.org/10.1038/s41467-017-01947-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mo J, Chen J, Zhang B (2020) Critical roles of FAM134B in ER-phagy and diseases. Cell Death Dis 11(11):983. https://doi.org/10.1038/s41419-020-03195-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Xing L, Son JH, Stevenson TJ, Lillesaar C, Bally-Cuif L, Dahl T, Bonkowsky JL (2015) A serotonin circuit acts as an environmental sensor to mediate midline axon crossing through EphrinB2. J Neurosci 35(44):14794–14808. https://doi.org/10.1523/JNEUROSCI.1295-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wimmer VC, Harty RC, Richards KL, Phillips AM, Miyazaki H, Nukina N, Petrou S (2015) Sodium channel β1 subunit localizes to axon initial segments of excitatory and inhibitory neurons and shows regional heterogeneity in mouse brain. J Comp Neurol 523(5):814–830. https://doi.org/10.1002/cne.23715

    Article  CAS  PubMed  Google Scholar 

  69. Bedogni F, Hodge RD, Elsen GE, Nelson BR, Daza RA, Beyer RP, Bammler TK, Rubenstein JL et al (2010) Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex. Proc Natl Acad Sci U S A 107(29):13129–13134. https://doi.org/10.1073/pnas.1002285107

    Article  PubMed  PubMed Central  Google Scholar 

  70. Chung CY, Licznerski P, Alavian KN, Simeone A, Lin Z, Martin E, Vance J, Isacson O (2010) The transcription factor orthodenticle homeobox 2 influences axonal projections and vulnerability of midbrain dopaminergic neurons. Brain 133(Pt 7):2022–2031. https://doi.org/10.1093/brain/awq142

    Article  PubMed  PubMed Central  Google Scholar 

  71. Blazejewski SM, Bennison SA, Liu X, Toyo-Oka K (2021) High-throughput kinase inhibitor screening reveals roles for Aurora and Nuak kinases in neurite initiation and dendritic branching. Sci Rep 11(1):8156. https://doi.org/10.1038/s41598-021-87521-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Beck HN, Drahushuk K, Jacoby DB, Higgins D, Lein PJ (2001) Bone morphogenetic protein-5 (BMP-5) promotes dendritic growth in cultured sympathetic neurons. BMC Neurosci 2:12. https://doi.org/10.1186/1471-2202-2-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cuenca-Bermejo L, Almela P, Navarro-Zaragoza J, Fernández Villalba E, González-Cuello A-M, Laorden M-L, Herrero M-T (2021) Cardiac changes in Parkinson’s disease: lessons from clinical and experimental evidence. Int J Mol Sci 22(24):13488. https://doi.org/10.3390/ijms222413488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hong CT, Chan L, Wu D, Chen WT, Chien LN (2019) Association between Parkinson’s disease and atrial fibrillation: a population-based study. Front Neurol 10:22. https://doi.org/10.3389/fneur.2019.00022

    Article  PubMed  PubMed Central  Google Scholar 

  75. Freyermuth F, Rau F, Kokunai Y et al (2016) Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nat Commun 7:11067. https://doi.org/10.1038/ncomms11067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pasquetti E, Lo Bianco M, Sullo F, Patanè F, Sciuto L, Polizzi A, Praticò A, Zanghì A et al (2021) SCN1B gene: a close relative to SCN1A. J Ped Neurol. https://doi.org/10.1055/s-0041-1727268

    Article  Google Scholar 

  77. Brackenbury WJ, Isom LL (2011) Na channel β subunits: overachievers of the ion channel family. Front Pharmacol 2:53. https://doi.org/10.3389/fphar.2011.00053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lin X, O’Malley H, Chen C, Auerbach D, Foster M, Shekhar A, Zhang M, Coetzee W et al (2015) Scn1b deletion leads to increased tetrodotoxin-sensitive sodium current, altered intracellular calcium homeostasis and arrhythmias in murine hearts. J Physiol 593(6):1389–1407. https://doi.org/10.1113/jphysiol.2014.277699

    Article  CAS  PubMed  Google Scholar 

  79. Ablinger C, Geisler SM, Stanika RI, Klein CT, Obermair GJ (2020) Neuronal α2δ proteins and brain disorders. Pflugers Arch 472(7):845–863. https://doi.org/10.1007/s00424-020-02420-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Cataldo S, Annoni GA, Marziliano N (2015) The perfect storm? Histiocytoid cardiomyopathy and compound CACNA2D1 and RANGRF mutation in a baby. Cardiol Young 25(1):174–176. https://doi.org/10.1017/S1047951113002382

    Article  PubMed  Google Scholar 

  81. Ramanan VK, Saykin AJ (2013) Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer’s disease, Parkinson’s disease, and related disorders. Am J Neurodegener Dis 2(3):145–175

    PubMed  PubMed Central  Google Scholar 

  82. Dolma S, Selvadurai HJ, Lan X, Lee L, Kushida M, Voisin V, Whetstone H, So M et al (2016) Inhibition of dopamine receptor D4 impedes autophagic flux, proliferation, and survival of glioblastoma stem cells. Cancer Cell 29(6):859–873. https://doi.org/10.1016/j.ccell.2016.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang Q, Dong X, Lu J, Hu T, Pei G (2020) Constitutive activity of a G protein-coupled receptor, DRD1, contributes to human cerebral organoid formation. Stem Cells 38(5):653–665. https://doi.org/10.1002/stem.3156

    Article  CAS  PubMed  Google Scholar 

  84. Jiang H, Ren Y, Yuen EY, Zhong P, Ghaedi M, Hu Z, Azabdaftari G, Nakaso K et al (2012) Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat Commun 3:668. https://doi.org/10.1038/ncomms1669

    Article  CAS  PubMed  Google Scholar 

  85. Jiang H, Jiang Q, Feng J (2004) Parkin increases dopamine uptake by enhancing the cell surface expression of dopamine transporter. J Biol Chem 279(52):54380–54386. https://doi.org/10.1074/jbc.M409282200

    Article  CAS  PubMed  Google Scholar 

  86. Peeler JC, Schedin-Weiss S, Soula M, Kazmi MA, Sakmar TP (2017) Isopeptide and ester bond ubiquitination both regulate degradation of the human dopamine receptor 4. J Biol Chem 292(52):21623–21630. https://doi.org/10.1074/jbc.M116.758961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Skieterska K, Rondou P, Van Craenenbroeck K (2016) Dopamine D4 receptor ubiquitination. Biochem Soc Trans 44(2):601–605. https://doi.org/10.1042/BST20150281

    Article  CAS  PubMed  Google Scholar 

  88. Juyal RC, Das M, Punia S, Behari M, Nainwal G, Singh S, Swaminath PV, Govindappa ST et al (2006) Genetic susceptibility to Parkinson’s disease among South and North Indians: I. Role of polymorphisms in dopamine receptor and transporter genes and association of DRD4 120-bp duplication marker. Neurogenetics 7:223–229. https://doi.org/10.1007/s10048-006-0048-y

    Article  CAS  PubMed  Google Scholar 

  89. Dipanwita S, Arindam B, Atanu B, Kunal R, Jharna R (2022) Genetic polymorphisms in DRD4 and risk for Parkinson’s disease among Eastern Indians. Neurol India 70(2):729–732. https://doi.org/10.4103/0028-3886.344670

    Article  PubMed  Google Scholar 

  90. Fernández-Santiago R, Carballo-Carbajal I, Castellano G, Torrent R, Richaud Y, Sánchez-Danés A, Vilarrasa-Blasi R, Sánchez-Pla A et al (2015) Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson’s disease patients. EMBO Mol Med 7(12):1529–1546. https://doi.org/10.15252/emmm.201505439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr. Y. Shevelyov (Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”) for critical reading of the manuscript and useful advice for its improvement and Dr. S. Kiselev (Vavilov Institute of General Genetics, Russian Academy of Sciences) for advice during generation of the resPD cell line. The study was performed using the equipment of the Center “Cellular and Genetic Technologies” of Institute of Molecular Genetics of the National Research Centre “Kurchatov Institute”.

Funding

This work was supported by the Ministry of Science and Higher Education of the Russian Federation (grant number 075–15-2021–1357 (to V.T. and E.N.), differentiation of cell lines; grant number 075–15-2019–1669 (to M.L.), generation of resPD cell line), by Russian Science Foundation (grant number 21–15-00103 (to V.T.), RNA-seq analysis), and by Russian Foundation for Basic Research (grant number 19–29-04080 (to V.N.), bioinformatic analysis).

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Author notes

  1. Olga Lebedeva, Daniil Poberezhniy, and Ekaterina Novosadova contributed equally to this work.

Authors and Affiliations

  1. Lopukhin Federal Research and Clinical Center of Physical Chemical Medicine of the Federal Medical and Biological Agency of the Russian Federation, Moscow, Russia

    Olga Lebedeva, Egor Volovikov, Ksenia Anufrieva & Maria Lagarkova

  2. Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia

    Olga Lebedeva, Ksenia Anufrieva & Maria Lagarkova

  3. Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, Moscow, Russia

    Daniil Poberezhniy, Ekaterina Novosadova, Tatiana Gerasimova, Lyudmila Novosadova, Elena Arsenyeva, Ekaterina Stepanenko, Darya Shimchenko, Igor Grivennikov, Vyacheslav Tarantul & Valentina Nenasheva

  4. Faculty of Biotechnology and Industrial Ecology, D.I. Mendeleyev University of Chemical Technology of Russia, Moscow, Russia

    Daniil Poberezhniy

  5. Research Center of Neurology, Moscow, Russia

    Sergey Illarioshkin

Authors
  1. Olga Lebedeva
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  2. Daniil Poberezhniy
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Contributions

V.N., E.N., and V.T. conceived the study. O.L. (supervised by M.L.) obtained the resPD iPSC line. E.N. (supervised by I.G.) and E.V. (supervised by O.L.) maintained and differentiated to NPs the cell lines used in the study. D.P. (with participation of K.A.) performed bioinformatic analysis. T.G. and E.S. carried out the Western-blot analysis. L.N. performed the RT-qPCR analysis. E.A. and D.S. (supervised by E.N.) performed immunostaining and quantification of cell cultures. S.I. provided fibroblast cells derived from PD patients. V.N. and T.G. wrote the draft of the manuscript with the input of all authors in the final version.

Corresponding authors

Correspondence to Tatiana Gerasimova or Valentina Nenasheva.

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Ethics Approval

The study complies with the World Medical Assembly Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. This work was approved by the Ethics Committee of the Institute of Molecular Genetics of the National Research Centre “Kurchatov Institute” (protocol №3 from February 19, 2018).

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Informed consent was obtained from all individual participants included in the study.

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The authors affirm that human research participants provided informed consent for publishing of tables and figures.

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The authors declare no competing interests.

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Lebedeva, O., Poberezhniy, D., Novosadova, E. et al. Overexpression of Parkin in the Neuronal Progenitor Cells from a Patient with Parkinson’s Disease Shifts the Transcriptome Towards the Normal State. Mol Neurobiol 60, 3522–3533 (2023). https://doi.org/10.1007/s12035-023-03293-z

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