Advertisement

Molecular Neurobiology

, Volume 55, Issue 6, pp 4689–4701 | Cite as

Systemic Analysis of miRNAs in PD Stress Condition: miR-5701 Modulates Mitochondrial–Lysosomal Cross Talk to Regulate Neuronal Death

  • Paresh Prajapati
  • Lakshmi Sripada
  • Kritarth Singh
  • Milton Roy
  • Khyati Bhatelia
  • Pooja Dalwadi
  • Rajesh Singh
Article

Abstract

Parkinson’s disease (PD) is complex neurological disorder and is prevalent in the elderly population. This is primarily due to loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) region of the brain. The modulators of the selective loss of dopaminergic neurons in PD are still not well understood. The small non-coding RNAs specifically miRNAs fine-tune the protein levels by post-transcriptional gene regulation. The role of miRNAs in PD pathogenesis is still not well characterized. In the current study, we identified the miRNA expression pattern in 6-OHDA-induced PD stress condition in SH-SY5Y, dopaminergic neuronal cell line. The targets of top 5 miRNAs both up- and down regulated were analyzed by using StarBase. The putative pathways of identified miRNAs included neurotrophin signaling, neuronal processes, mTOR, and cell death. The level of miR-5701 was significantly downregulated in the presence of 6-OHDA. The putative targets of miR-5701 miRNA include genes involved in lysosomal biogenesis and mitochondrial quality control. The transfection of miR-5701 mimic decreased the transcript level of VCP, LAPTM4A, and ATP6V0D1. The expression of miR-5701 mimic induces mitochondrial dysfunction, defect in autophagy flux, and further sensitizes SH-SY5Y cells to 6-OHDA-induced cell death. To our knowledge, the evidence in the current study demonstrated the dysregulation of specific pattern of miRNAs in PD stress conditions. We further characterized the role of miR-5701, a novel miRNA, as a potential regulator of the mitochondrial and lysosomal function determining the fate of neurons which has important implication in the pathogenesis of PD.

Keywords

Autophagy flux Lysosome miRNA Parkinson’s disease Mitochondria 

Notes

Acknowledgements

This work was financially supported by the Department of Biotechnology, Government of India (Grant number BT/PR14206/MED/30/396/2010 to Rajesh Singh). This work constitutes the Ph.D. thesis of Paresh Prajapati. Lakshmi Sripada and Kritarth Singh received their Senior Research fellowship from University Grants Commission (UGC), Govt. of India. Khyati Bhatelia received her Senior Research fellowship from Council of Scientific and Industrial Research (CSIR), Govt. of India. Dhruv Gohel help in maintenance of SH-SY5Y cell and transfection during revision of the manuscript is acknowledged. The authors also acknowledge the instrumentation facility by DBT MSUB ILSPARE.

Compliance with Ethical Standards

Conflict of Interest

There are no any competing financial interests in relation to the work described.

Supplementary material

12035_2017_664_MOESM1_ESM.pdf (225 kb)
Fig. S1 (PDF 224 kb)
12035_2017_664_MOESM2_ESM.pdf (280 kb)
Fig. S2 (PDF 280 kb)
12035_2017_664_MOESM3_ESM.pdf (174 kb)
Fig. S3 (PDF 173 kb)
12035_2017_664_MOESM4_ESM.pdf (152 kb)
Fig. S4 (PDF 152 kb)
12035_2017_664_MOESM5_ESM.pdf (191 kb)
Fig. S5 (PDF 191 kb)
12035_2017_664_MOESM6_ESM.pdf (381 kb)
Table S1 (PDF 381 kb)
12035_2017_664_MOESM7_ESM.pdf (405 kb)
Table S2 (PDF 404 kb)
12035_2017_664_MOESM8_ESM.pdf (297 kb)
Table S3 (PDF 296 kb)

References

  1. 1.
    Beitz JM (2014) Parkinson's disease: a review. Front Biosci 6:65–74CrossRefGoogle Scholar
  2. 2.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388(6645):839–840. doi: 10.1038/42166 CrossRefPubMedGoogle Scholar
  3. 3.
    Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS et al (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38(5):515–517. doi: 10.1038/ng1769 CrossRefPubMedGoogle Scholar
  4. 4.
    Lang AE, Lozano AM (1998) Parkinson's disease. Second of two parts. N Engl J Med 339(16):1130–1143. doi: 10.1056/NEJM199810153391607 CrossRefPubMedGoogle Scholar
  5. 5.
    Schapira AH (1993) Mitochondrial complex I deficiency in Parkinson's disease. Adv Neurol 60:288–291PubMedGoogle Scholar
  6. 6.
    Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A 80(14):4546–4550CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chen H, Chan DC (2009) Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet 18(R2):R169–R176. doi: 10.1093/hmg/ddp326 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gomes LC, Scorrano L (2013) Mitochondrial morphology in mitophagy and macroautophagy. Biochim Biophys Acta 1833(1):205–212. doi: 10.1016/j.bbamcr.2012.02.012 CrossRefPubMedGoogle Scholar
  9. 9.
    Pickrell AM, Youle RJ (2015) The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease. Neuron 85(2):257–273. doi: 10.1016/j.neuron.2014.12.007 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Deas E, Wood NW, Plun-Favreau H (2011) Mitophagy and Parkinson's disease: the PINK1-parkin link. Biochim Biophys Acta 1813(4):623–633. doi: 10.1016/j.bbamcr.2010.08.007 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kinghorn KJ, Asghari AM, Castillo-Quan JI (2017) The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease. Neural Regen Res 12(3):380–384. doi: 10.4103/1673-5374.202934 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Tran N, Hutvagner G (2013) Biogenesis and the regulation of the maturation of miRNAs. Essays Biochem 54:17–28. doi: 10.1042/bse0540017 CrossRefPubMedGoogle Scholar
  13. 13.
    Sripada L, Singh K, Lipatova AV, Singh A, Prajapati P, Tomar D, Bhatelia K, Roy M et al (2017) hsa-miR-4485 regulates mitochondrial functions and inhibits the tumorigenicity of breast cancer cells. J Mol Med 95(6):641–651. doi: 10.1007/s00109-017-1517-5 CrossRefPubMedGoogle Scholar
  14. 14.
    Sripada L, Tomar D, Prajapati P, Singh R, Singh AK, Singh R (2012) Systematic analysis of small RNAs associated with human mitochondria by deep sequencing: detailed analysis of mitochondrial associated miRNA. PLoS One 7(9):e44873. doi: 10.1371/journal.pone.0044873 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Duarte FV, Palmeira CM, Rolo AP (2014) The role of microRNAs in mitochondria: small players acting wide. Genes 5(4):865–886. doi: 10.3390/genes5040865 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Li P, Jiao J, Gao G, Prabhakar BS (2012) Control of mitochondrial activity by miRNAs. J Cell Biochem 113(4):1104–1110. doi: 10.1002/jcb.24004 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y et al (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19(21):5720–5728. doi: 10.1093/emboj/19.21.5720 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Prajapati P, Sripada L, Singh K, Bhatelia K, Singh R, Singh R (2015) TNF-alpha regulates miRNA targeting mitochondrial complex-I and induces cell death in dopaminergic cells. Biochim Biophys Acta 1852(3):451–461. doi: 10.1016/j.bbadis.2014.11.019 CrossRefPubMedGoogle Scholar
  19. 19.
    Orom UA, Lund AH (2007) Isolation of microRNA targets using biotinylated synthetic microRNAs. Methods 43(2):162–165. doi: 10.1016/j.ymeth.2007.04.007 CrossRefPubMedGoogle Scholar
  20. 20.
    Li JH, Liu S, Zhou H, Qu LH, Yang JH (2014) starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res 42(Database issue):D92–D97. doi: 10.1093/nar/gkt1248 CrossRefPubMedGoogle Scholar
  21. 21.
    Luthman J, Fredriksson A, Sundstrom E, Jonsson G, Archer T (1989) Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage. Behav Brain Res 33(3):267–277CrossRefPubMedGoogle Scholar
  22. 22.
    Berndt N, Holzhutter HG, Bulik S (2013) Implications of enzyme deficiencies on mitochondrial energy metabolism and reactive oxygen species formation of neurons involved in rotenone-induced Parkinson's disease: a model-based analysis. FEBS J 280(20):5080–5093. doi: 10.1111/febs.12480 CrossRefPubMedGoogle Scholar
  23. 23.
    Yang JH, Li JH, Shao P, Zhou H, Chen YQ, Qu LH (2011) starBase: a database for exploring microRNA-mRNA interaction maps from Argonaute CLIP-Seq and Degradome-Seq data. Nucleic Acids Res 39(Database issue):D202–D209. doi: 10.1093/nar/gkq1056 CrossRefPubMedGoogle Scholar
  24. 24.
    Ludtmann MH, Arber C, Bartolome F, de Vicente M, Preza E, Carro E, Houlden H, Gandhi S et al (2017) Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and impair energy metabolism in human neurons. J Biol Chem. doi: 10.1074/jbc.M116.762898
  25. 25.
    Guo X, Sun X, Hu D, Wang YJ, Fujioka H, Vyas R, Chakrapani S, Joshi AU et al (2016) VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington's disease. Nat Commun 7:12646. doi: 10.1038/ncomms12646 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Johnson AE, Shu H, Hauswirth AG, Tong A, Davis GW. VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo. eLife 2015:4. doi: 10.7554/eLife.07366.
  27. 27.
    Fang L, Hemion C, Pinho Ferreira Bento AC, Bippes CC, Flammer J, Neutzner A (2015) Mitochondrial function in neuronal cells depends on p97/VCP/Cdc48-mediated quality control. Front Cell Neurosci 9:16. doi: 10.3389/fncel.2015.00016 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kim NC, Tresse E, Kolaitis RM, Molliex A, Thomas RE, Alami NH, Wang B, Joshi A et al (2013) VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron 78(1):65–80. doi: 10.1016/j.neuron.2013.02.029 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Bartolome F, Wu HC, Burchell VS, Preza E, Wray S, Mahoney CJ, Fox NC, Calvo A et al (2013) Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron 78(1):57–64. doi: 10.1016/j.neuron.2013.02.028 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Stowe DF, Camara AK (2009) Mitochondrial reactive oxygen species production in excitable cells: modulators of mitochondrial and cell function. Antioxid Redox Signal 11(6):1373–1414. doi: 10.1089/ARS.2008.2331 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Malik AN, Shahni R, Rodriguez-de-Ledesma A, Laftah A, Cunningham P (2011) Mitochondrial DNA as a non-invasive biomarker: accurate quantification using real time quantitative PCR without co-amplification of pseudogenes and dilution bias. Biochem Biophys Res Commun 412(1):1–7. doi: 10.1016/j.bbrc.2011.06.067 CrossRefPubMedGoogle Scholar
  32. 32.
    Ashrafi G, Schwarz TL (2013) The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ 20(1):31–42. doi: 10.1038/cdd.2012.81 CrossRefPubMedGoogle Scholar
  33. 33.
    Dargemont C, Ossareh-Nazari B (2012) Cdc48/p97, a key actor in the interplay between autophagy and ubiquitin/proteasome catabolic pathways. Biochim Biophys Acta 1823(1):138–144. doi: 10.1016/j.bbamcr.2011.07.011 CrossRefPubMedGoogle Scholar
  34. 34.
    Tresse E, Salomons FA, Vesa J, Bott LC, Kimonis V, Yao TP, Dantuma NP, Taylor JP (2010) VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 6(2):217–227CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ju JS, Fuentealba RA, Miller SE, Jackson E, Piwnica-Worms D, Baloh RH, Weihl CC (2009) Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 187(6):875–888. doi: 10.1083/jcb.200908115 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhou J, Tan SH, Nicolas V, Bauvy C, Yang ND, Zhang J, Xue Y, Codogno P et al (2013) Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion. Cell Res 23(4):508–523. doi: 10.1038/cr.2013.11 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Crider BP, Xie XS, Stone DK (1994) Bafilomycin inhibits proton flow through the H+ channel of vacuolar proton pumps. J Biol Chem 269(26):17379–17381PubMedGoogle Scholar
  38. 38.
    Hu Y, Lan W, Miller D (2017) Next-generation sequencing for MicroRNA expression profile. Methods Mol Biol 1617:169–177. doi: 10.1007/978-1-4939-7046-9_12 CrossRefPubMedGoogle Scholar
  39. 39.
    Li H, Mao S, Wang H, Zen K, Zhang C, Li L (2014) MicroRNA-29a modulates axon branching by targeting doublecortin in primary neurons. Protein & cell 5(2):160–169. doi: 10.1007/s13238-014-0022-7 CrossRefGoogle Scholar
  40. 40.
    Hu Z, Yu D, Gu QH, Yang Y, Tu K, Zhu J, Li Z (2014) miR-191 and miR-135 are required for long-lasting spine remodelling associated with synaptic long-term depression. Nat Commun 5:3263. doi: 10.1038/ncomms4263 PubMedPubMedCentralGoogle Scholar
  41. 41.
    Kaplan BB, Kar AN, Gioio AE, Aschrafi A (2013) MicroRNAs in the axon and presynaptic nerve terminal. Front Cell Neurosci 7:126. doi: 10.3389/fncel.2013.00126 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Dajas-Bailador F, Bonev B, Garcez P, Stanley P, Guillemot F, Papalopulu N (2012) microRNA-9 regulates axon extension and branching by targeting Map1b in mouse cortical neurons. Nat Neurosci. doi: 10.1038/nn.3082
  43. 43.
    Recasens A, Perier C, Sue CM (2016) Role of microRNAs in the regulation of alpha-Synuclein expression: a systematic review. Front Mol Neurosci 9:128. doi: 10.3389/fnmol.2016.00128 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Marques TM, Kuiperij HB, Bruinsma IB, van Rumund A, Aerts MB, Esselink RA, Bloem BR, Verbeek MM (2016) MicroRNAs in cerebrospinal fluid as potential biomarkers for Parkinson's disease and multiple system atrophy. Mol Neurobiol. doi: 10.1007/s12035-016-0253-0
  45. 45.
    Hoss AG, Labadorf A, Beach TG, Latourelle JC, Myers RH (2016) microRNA profiles in Parkinson's disease prefrontal cortex. Front Aging Neurosci 8:36. doi: 10.3389/fnagi.2016.00036 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Majounie E, Traynor BJ, Chio A, Restagno G, Mandrioli J, Benatar M, Taylor JP, Singleton AB (2012) Mutational analysis of the VCP gene in Parkinson's disease. Neurobiol Aging 33(1):209 e201–209 e202. doi: 10.1016/j.neurobiolaging.2011.07.011 CrossRefGoogle Scholar
  47. 47.
    Chan N, Le C, Shieh P, Mozaffar T, Khare M, Bronstein J, Kimonis V (2012) Valosin-containing protein mutation and Parkinson's disease. Parkinsonism Relat Disord 18(1):107–109. doi: 10.1016/j.parkreldis.2011.07.006 CrossRefPubMedGoogle Scholar
  48. 48.
    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. doi: 10.1083/jcb.201007013 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Valm AM, Cohen S, Legant WR, Melunis J, Hershberg U, Wait E, Cohen AR, Davidson MW et al (2017) Applying systems-level spectral imaging and analysis to reveal the organelle interactome. Nature. doi: 10.1038/nature22369
  50. 50.
    Demers-Lamarche J, Guillebaud G, Tlili M, Todkar K, Belanger N, Grondin M, Nguyen AP, Michel J et al (2016) Loss of mitochondrial function impairs lysosomes. J Biol Chem 291(19):10263–10276. doi: 10.1074/jbc.M115.695825 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Baixauli F, Acin-Perez R, Villarroya-Beltri C, Mazzeo C, Nunez-Andrade N, Gabande-Rodriguez E, Ledesma MD, Blazquez A et al (2015) Mitochondrial respiration controls lysosomal function during inflammatory T cell responses. Cell Metab 22(3):485–498. doi: 10.1016/j.cmet.2015.07.020 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Hogue DL, Nash C, Ling V, Hobman TC (2002) Lysosome-associated protein transmembrane 4 alpha (LAPTM4 alpha) requires two tandemly arranged tyrosine-based signals for sorting to lysosomes. The Biochemical journal 365(Pt 3):721–730. doi: 10.1042/BJ20020205 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Agarwal AK, White PC (2000) Structure of the VPATPD gene encoding subunit D of the human vacuolar proton ATPase. Biochem Biophys Res Commun 279(2):543–547. doi: 10.1006/bbrc.2000.4003 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Biochemistry, Faculty of ScienceThe Maharaja Sayajirao University of BarodaVadodaraIndia

Personalised recommendations