Potential biomarker identification for Friedreich’s ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion
Autoři:
Marissa Z. McMackin aff001; Blythe Durbin-Johnson aff002; Marek Napierala aff003; Jill S. Napierala aff003; Luis Ruiz aff001; Eleonora Napoli aff001; Susan Perlman aff004; Cecilia Giulivi aff001; Gino A. Cortopassi aff001
Působiště autorů:
Department of Molecular Biosciences, University of California, Davis, Davis, California, United States of America
aff001; Bioinformatics, University of California, Davis, Davis, California, United States of America
aff002; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
aff003; Department of Neurology, University of California, Los Angeles, Los Angeles, California, United States of America
aff004
Vyšlo v časopise:
PLoS ONE 14(10)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0223209
Souhrn
Friedreich’s ataxia (FA) is a neurodegenerative disease with no approved therapy that is the result of frataxin deficiency. The identification of human FA blood biomarkers related to disease severity and neuro-pathomechanism could support clinical trials of drug efficacy. To try to identify human biomarkers of neuro-pathomechanistic relevance, we compared the overlapping gene expression changes of primary blood and skin cells of FA patients with changes in the Dorsal Root Ganglion (DRG) of the KIKO FA mouse model. As DRG is the primary site of neurodegeneration in FA, our goal was to identify which changes in blood and skin of FA patients provide a 'window' into the FA neuropathomechanism inside the nervous system. In addition, gene expression in frataxin-deficient neuroglial cells and FA mouse hearts were compared for a total of 5 data sets. The overlap of these changes strongly supports mitochondrial changes, apoptosis and alterations of selenium metabolism. Consistent biomarkers were observed, including three genes of mitochondrial stress (MTIF2, ENO2), apoptosis (DDIT3/CHOP), oxidative stress (PREX1), and selenometabolism (SEPW1). These results prompted our investigation of the GPX1 activity as a marker of selenium and oxidative stress, in which we observed a significant change in FA patients. We believe these lead biomarkers that could be assayed in FA patient blood as indicators of disease severity and progression, and also support the involvement of mitochondria, apoptosis and selenium in the neurodegenerative process.
Klíčová slova:
Gene expression – Blood – Mouse models – Mitochondria – Apoptosis – Biomarkers – Antioxidants – Selenium
Zdroje
1. Pandolfo M. Friedreich’s ataxia: clinical aspects and pathogenesis. Semin Neurol. 1999;19(3):311–21. Epub 2002/08/27. doi: 10.1055/s-2008-1040847 12194387.
2. Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, et al. Frataxin is Reduced in Friedreich Ataxia Patients and is Associated with Mitochondrial Membranes. Human Molecular Genetics. 1997;6(11):1771–80. doi: 10.1093/hmg/6.11.1771 9302253
3. Durr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med. 1996;335(16):1169–75. Epub 1996/10/17. doi: 10.1056/NEJM199610173351601 8815938.
4. Napoli E, Taroni F, Cortopassi GA. Frataxin, iron-sulfur clusters, heme, ROS, and aging. Antioxid Redox Signal. 2006;8(3–4):506–16. Epub 2006/05/09. doi: 10.1089/ars.2006.8.506 16677095.
5. Filla A, De Michele G, Cavalcanti F, Pianese L, Monticelli A, Campanella G, et al. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet. 1996;59(3):554–60. 8751856.
6. Marmolino D. Friedreich’s ataxia: past, present and future. Brain Res Rev. 2011;67(1–2):311–30. Epub 2011/05/10. doi: 10.1016/j.brainresrev.2011.04.001 21550666.
7. De Biase I, Rasmussen A, Endres D, Al-Mahdawi S, Monticelli A, Cocozza S, et al. Progressive gaa expansions in dorsal root ganglia of Friedreich’s ataxia patients. Annals of Neurology. 2007;61(1):55–60. doi: 10.1002/ana.21052 17262846
8. Pandolfo M. Friedreich ataxia: the clinical picture. Journal of neurology. 2009;256 Suppl 1:3–8. Epub 2009/04/11. doi: 10.1007/s00415-009-1002-3 19283344.
9. Delatycki MB, Paris DB, Gardner RJ, Nicholson GA, Nassif N, Storey E, et al. Clinical and genetic study of Friedreich ataxia in an Australian population. Am J Med Genet. 1999;87(2):168–74. Epub 1999/10/26. doi: 10.1002/(sici)1096-8628(19991119)87:2<168::aid-ajmg8>3.0.co;2-2 10533031.
10. Rigaud M, Gemes G, Barabas ME, Chernoff DI, Abram SE, Stucky CL, et al. Species and strain differences in rodent sciatic nerve anatomy: Implications for studies of neuropathic pain. Pain. 2008;136(1–2):188–201. doi: 10.1016/j.pain.2008.01.016 18316160.
11. Miranda CJ, Santos MM, Ohshima K, Smith J, Li L, Bunting M, et al. Frataxin knockin mouse. FEBS Lett. 2002;512(1–3):291–7. Epub 2002/02/20. doi: 10.1016/s0014-5793(02)02251-2 11852098.
12. McMackin MZ, Henderson CK, Cortopassi GA. Neurobehavioral deficits in the KIKO mouse model of Friedreich’s ataxia. Behav Brain Res. 2017;316:183–8. Epub 2016/08/31. doi: 10.1016/j.bbr.2016.08.053 27575947.
13. Jasoliya MJ, McMackin MZ, Henderson CK, Perlman SL, Cortopassi GA. Frataxin Deficiency Impairs Mitochondrial Biogenesis in Cells, Mice and Humans. Hum Mol Genet. 2017. Epub 2017/04/27. doi: 10.1093/hmg/ddx141 28444186.
14. Evans-Galea MV, Lockhart PJ, Galea CA, Hannan AJ, Delatycki MB. Beyond loss of frataxin: the complex molecular pathology of Friedreich ataxia. Discov Med. 2014;17(91):25–35. Epub 2014/01/15. 24411698.
15. Santos R, Lefevre S, Sliwa D, Seguin A, Camadro JM, Lesuisse E. Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities. Antioxid Redox Signal. 2010;13(5):651–90. doi: 10.1089/ars.2009.3015 20156111.
16. Nachun D, Gao F, Isaacs C, Strawser C, Yang Z, Dokuru D, et al. Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich’s ataxia patients. Hum Mol Genet. 2018. Epub 2018/05/24. doi: 10.1093/hmg/ddy198 29790959.
17. Li Y, Lu Y, Polak U, Lin K, Shen J, Farmer J, et al. Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus. Hum Mol Genet. 2015;24(24):6932–43. Epub 2015/09/25. doi: 10.1093/hmg/ddv397 26401053.
18. Napierala JS, Li Y, Lu Y, Lin K, Hauser LA, Lynch DR, et al. Comprehensive analysis of gene expression patterns in Friedreich’s ataxia fibroblasts by RNA sequencing reveals altered levels of protein synthesis factors and solute carriers. 2017;10(11):1353–69. doi: 10.1242/dmm.030536 29125828.
19. Sleigh JN, Weir GA, Schiavo G. A simple, step-by-step dissection protocol for the rapid isolation of mouse dorsal root ganglia. BMC Res Notes. 2016;9. doi: 10.1186/s13104-016-1915-8 26864470.
20. Wang Y, Ghaffari N, Johnson CD, Braga-Neto UM, Wang H, Chen R, et al. Evaluation of the coverage and depth of transcriptome by RNA-Seq in chickens. BMC Bioinformatics. 2011;12(10):S5. doi: 10.1186/1471-2105-12-S10-S5 22165852
21. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biology. 2013;14(4):R36. doi: 10.1186/gb-2013-14-4-r36 23618408
22. Roberts A, Pimentel H, Trapnell C, Pachter L. Identification of novel transcripts in annotated genomes using RNA-Seq. Bioinformatics. 2011;27(17):2325–9. Epub 2011/06/24. doi: 10.1093/bioinformatics/btr355 21697122.
23. Anders S, Pyl PT, Huber W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166–9. Epub 2014/09/28. doi: 10.1093/bioinformatics/btu638 25260700.
24. Lu C, Schoenfeld R, Shan Y, Tsai C, Hammock B, Cortopassi G. Frataxin Deficiency Induces Schwann Cell Inflammation and Death. Biochim Biophys Acta. 2009;1792(11):1052–61. doi: 10.1016/j.bbadis.2009.07.011 19679182.
25. Schoenfeld RA, Napoli E, Wong A, Zhan S, Reutenauer L, Morin D, et al. Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells. Hum Mol Genet. 2005;14(24):3787–99. Epub 2005/10/22. doi: 10.1093/hmg/ddi393 16239244.
26. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 2013;41(Database issue):D808–15. Epub 2012/12/04. doi: 10.1093/nar/gks1094 23203871.
27. Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57. Epub 2009/01/10. doi: 10.1038/nprot.2008.211 19131956.
28. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Research. 2016. doi: 10.1093/nar/gkw377 27141961
29. Igoillo-Esteve M, Gurgul-Convey E, Hu A, Romagueira Bichara Dos Santos L, Abdulkarim B, Chintawar S, et al. Unveiling a common mechanism of apoptosis in β-cells and neurons in Friedreich’s ataxia. Human Molecular Genetics. 2015;24(8):2274–86. doi: 10.1093/hmg/ddu745 25552656
30. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6(5):1099–108. Epub 2000/12/07. doi: 10.1016/s1097-2765(00)00108-8 11106749.
31. Oyadomari S, Mori M. Roles of CHOP//GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2003;11(4):381–9.
32. Paschen W, Proud CG, Mies G. Shut-down of translation, a global neuronal stress response: mechanisms and pathological relevance. Curr Pharm Des. 2007;13(18):1887–902. Epub 2007/06/23. doi: 10.2174/138161207780858401 17584115.
33. Sok J, Wang XZ, Batchvarova N, Kuroda M, Harding H, Ron D. CHOP-Dependent Stress-Inducible Expression of a Novel Form of Carbonic Anhydrase VI. Mol Cell Biol. 1999;19(1):495–504. doi: 10.1128/mcb.19.1.495 9858573.
34. Silva JM, Wong A, Carelli V, Cortopassi GA. Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia. Neurobiol Dis. 2009;34(2):357–65. Epub 2009/02/24. doi: 10.1016/j.nbd.2009.02.005 19233273.
35. Kaul G, Pattan G, Rafeequi T. Eukaryotic elongation factor-2 (eEF2): its regulation and peptide chain elongation. Cell biochemistry and function. 2011;29(3):227–34. Epub 2011/03/12. doi: 10.1002/cbf.1740 21394738.
36. Steinbrenner H, Speckmann B, Klotz LO. Selenoproteins: Antioxidant selenoenzymes and beyond. Arch Biochem Biophys. 2016;595:113–9. Epub 2016/04/21. doi: 10.1016/j.abb.2015.06.024 27095226.
37. De Spirt S, Eckers A, Wehrend C, Micoogullari M, Sies H, Stahl W, et al. Interplay between the chalcone cardamonin and selenium in the biosynthesis of Nrf2-regulated antioxidant enzymes in intestinal Caco-2 cells. Free Radic Biol Med. 2016;91:164–71. Epub 2015/12/25. doi: 10.1016/j.freeradbiomed.2015.12.011 26698667.
38. Combs G. Who Can Benefit from Selenium? Diversity of Selenium Functions in Health and Disease. Oxidative Stress and Disease: CRC Press; 2015. p. 3–16.
39. Gladyshev VN, Arner ES, Berry MJ, Brigelius-Flohe R, Bruford EA, Burk RF, et al. Selenoprotein Gene Nomenclature. J Biol Chem. 2016;291(46):24036–40. Epub 2016/09/21. doi: 10.1074/jbc.M116.756155 27645994.
40. Brigelius-Flohe R, Flohe L. Selenium and redox signaling. Arch Biochem Biophys. 2016. Epub 2016/08/09. doi: 10.1016/j.abb.2016.08.003 27495740.
41. Brigelius-Flohe R. The evolving versatility of selenium in biology. Antioxid Redox Signal. 2015;23(10):757–60. Epub 2015/09/26. doi: 10.1089/ars.2015.6469 26406357.
42. Steinbrenner H. Interference of selenium and selenoproteins with the insulin-regulated carbohydrate and lipid metabolism. Free radical biology & medicine. 2013;65:1538–47. Epub 2013/07/23. doi: 10.1016/j.freeradbiomed.2013.07.016 23872396.
43. Auchere F, Santos R, Planamente S, Lesuisse E, Camadro JM. Glutathione-dependent redox status of frataxin-deficient cells in a yeast model of Friedreich’s ataxia. Hum Mol Genet. 2008;17(18):2790–802. Epub 2008/06/20. doi: 10.1093/hmg/ddn178 18562474.
44. Abeti R, Parkinson MH, Hargreaves IP, Angelova PR, Sandi C, Pook MA, et al. 'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich/’s ataxia'. Cell Death Dis. 2016;7:e2237. doi: 10.1038/cddis.2016.111 27228352
45. Fryer MJ. Rationale for clinical trials of selenium as an antioxidant for the treatment of the cardiomyopathy of Friedreich’s ataxia. Medical hypotheses. 2002;58(2):127–32. Epub 2002/01/29. doi: 10.1054/mehy.2001.1474 11812188.
46. Yim H-S, Cho YS, Guang X, Kang SG, Jeong J-Y, Cha S-S, et al. Minke whale genome and aquatic adaptation in cetaceans. Nat Genet. 2014;46(1):88–92. http://www.nature.com/ng/journal/v46/n1/abs/ng.2835.html#supplementary-information. 24270359
47. Dato S, De Rango F. Antioxidants and Quality of Aging: Further Evidences for a Major Role of TXNRD1 Gene Variability on Physical Performance at Old Age. 2015;2015:926067. doi: 10.1155/2015/926067 26064428.
48. Kiermayer C, Michalke B, Schmidt J, Brielmeier M. Effect of selenium on thioredoxin reductase activity in Txnrd1 or Txnrd2 hemizygous mice. Biol Chem. 2007;388(10):1091–7. Epub 2007/10/17. doi: 10.1515/BC.2007.133 17937623.
49. Shan Y, Schoenfeld RA, Hayashi G, Napoli E, Akiyama T, Iodi Carstens M, et al. Frataxin Deficiency Leads to Defects in Expression of Antioxidants and Nrf2 Expression in Dorsal Root Ganglia of the Friedreich’s Ataxia YG8R Mouse Model. Antioxidants & redox signaling. 2013;19(13):1481–93. doi: 10.1089/ars.2012.4537 23350650.
50. Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, et al. The Friedreich’s ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet. 1999;8(3):425–30. Epub 1999/02/09. doi: 10.1093/hmg/8.3.425 9949201.
51. Chantrel-Groussard K, Geromel V, Puccio H, Koenig M, Munnich A, Rotig A, et al. Disabled early recruitment of antioxidant defenses in Friedreich’s ataxia. Hum Mol Genet. 2001;10(19):2061–7. Epub 2001/10/09. doi: 10.1093/hmg/10.19.2061 11590123.
52. Takano K, Shiba N, Wakui K, Yamaguchi T, Aida N, Inaba Y, et al. Elevation of neuron specific enolase and brain iron deposition on susceptibility-weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood: Additional case report and review of the literature. Am J Med Genet A. 2016;170a(2):322–8. Epub 2015/10/21. doi: 10.1002/ajmg.a.37432 26481852.
53. Sasser T, Qiu QS, Karunakaran S, Padolina M, Reyes A, Flood B, et al. Yeast lipin 1 orthologue pah1p regulates vacuole homeostasis and membrane fusion. The Journal of biological chemistry. 2012;287(3):2221–36. Epub 2011/11/29. doi: 10.1074/jbc.M111.317420 22121197.
54. Bego T, Dujic T, Mlinar B, Semiz S, Malenica M, Prnjavorac B, et al. Association of LPIN1 gene variations with markers of metabolic syndrome in population from Bosnia and Herzegovina. Med Glas (Zenica). 2015;12(2):113–21. Epub 2015/08/16. 26276647.
55. Sanchez N, Chapdelaine P, Rousseau J, Raymond F, Corbeil J, Tremblay JP. Characterization of frataxin gene network in Friedreich’s ataxia fibroblasts using the RNA-Seq technique. Mitochondrion. 2016;30:59–66. http://dx.doi.org/10.1016/j.mito.2016.06.003. 27350085
56. Groh M, Lufino MM, Wade-Martins R, Gromak N. R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome. PLoS Genet. 2014;10(5):e1004318. Epub 2014/05/03. doi: 10.1371/journal.pgen.1004318 24787137.
57. Stemmler TL, Lesuisse E, Pain D, Dancis A. Frataxin and Mitochondrial FeS Cluster Biogenesis. J Biol Chem. 2010;285(35):26737–43. doi: 10.1074/jbc.R110.118679 20522547.
58. Audano M, Ferrari A, Fiorino E, Kuenzl M, Caruso D, Mitro N, et al. Energizing Genetics and Epi-genetics: Role in the Regulation of Mitochondrial Function. Curr Genomics. 2014;15(6):436–56. doi: 10.2174/138920291506150106151119 25646072.
59. Smits P, Smeitink J, van den Heuvel L. Mitochondrial Translation and Beyond: Processes Implicated in Combined Oxidative Phosphorylation Deficiencies. Journal of Biomedicine and Biotechnology. 2010;2010:24. doi: 10.1155/2010/737385 20396601
60. Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001;2(5):342–52. http://www.nature.com/nrg/journal/v2/n5/suppinfo/nrg0501_342a_S1.html. 11331900
61. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973;179(4073):588–90. Epub 1973/02/09. doi: 10.1126/science.179.4073.588 4686466.
62. Piemonte F, Pastore A, Tozzi G, Tagliacozzi D, Santorelli FM, Carrozzo R, et al. Glutathione in blood of patients with Friedreich’s ataxia. Eur J Clin Invest. 2001;31(11):1007–11. Epub 2001/12/12. doi: 10.1046/j.1365-2362.2001.00922.x 11737244.
63. Helveston W, Hurd R, Uthman B, Wilder BJ. Abnormalities of glutathione peroxidase and glutathione reductase in four patients with Friedreich’s disease. Mov Disord. 1996;11(1):106–7. Epub 1996/01/01. doi: 10.1002/mds.870110124 8771081.
64. Baker RD, Baker SS, LaRosa K, Whitney C, Newburger PE. Selenium regulation of glutathione peroxidase in human hepatoma cell line Hep3B. Arch Biochem Biophys. 1993;304(1):53–7. Epub 1993/07/01. doi: 10.1006/abbi.1993.1320 8391784.
65. Kirches E, Andrae N, Hoefer A, Kehler B, Zarse K, Leverkus M, et al. Dual role of the mitochondrial protein frataxin in astrocytic tumors. Lab Invest. 2011;91(12):1766–76. doi: 10.1038/labinvest.2011.130 21863062
66. Jauslin ML, Wirth T, Meier T, Schoumacher F. A cellular model for Friedreich Ataxia reveals small-molecule glutathione peroxidase mimetics as novel treatment strategy. Hum Mol Genet. 2002;11(24):3055–63. Epub 2002/11/06. doi: 10.1093/hmg/11.24.3055 12417527.
67. Kohrl J, Brigelius-Flohe R, Bock A, Gartner R, Meyer O, Flohe L. Selenium in biology: facts and medical perspectives. Biol Chem. 2000;381(9–10):849–64. Epub 2000/11/15. doi: 10.1515/BC.2000.107 11076017.
68. Brigelius-Flohe R, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta. 2013;1830(5):3289–303. Epub 2012/12/04. doi: 10.1016/j.bbagen.2012.11.020 23201771.
69. Tinggi U. Selenium: its role as antioxidant in human health. Environ Health Prev Med. 2008;13(2):102–8. doi: 10.1007/s12199-007-0019-4 19568888.
70. Carletti B, Piemonte F. Friedreich’s Ataxia: A Neuronal Point of View on the Oxidative Stress Hypothesis. Antioxidants. 2014;3(3):592–603. doi: 10.3390/antiox3030592 26785073.
71. Ishihara H, Kanda F, Matsushita T, Chihara K, Itoh K. White muscle disease in. J Neurol Neurosurg Psychiatry. 1999;67(6):829–30. doi: 10.1136/jnnp.67.6.829 10617385.
72. Koller LD, Exon JH. The two faces of selenium-deficiency and toxicity—are similar in animals and man. Can J Vet Res. 1986;50(3):297–306. Epub 1986/07/01. 3527390.
73. Kipp AP, Frombach J, Deubel S, Brigelius-Flohe R. Selenoprotein W as biomarker for the efficacy of selenium compounds to act as source for selenoprotein biosynthesis. Methods in enzymology. 2013;527:87–112. Epub 2013/07/09. doi: 10.1016/B978-0-12-405882-8.00005-2 23830627.
74. Dillon LM, Bean JR, Yang W, Shee K, Symonds LK, Balko JM, et al. P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT, and MEK/ERK signaling in breast cancer. Oncogene. 2015;34(30):3968–76. doi: 10.1038/onc.2014.328 25284585.
75. Damoulakis G, Gambardella L, Rossman KL, Lawson CD, Anderson KE, Fukui Y, et al. P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils. Journal of Cell Science. 2014;127(11):2589–600. doi: 10.1242/jcs.153049 24659802
76. Hayashi G, Cortopassi G. Lymphoblast Oxidative Stress Genes as Potential Biomarkers of Disease Severity and Drug Effect in Friedreich’s Ataxia. PLoS ONE. 2016;11(4). doi: 10.1371/journal.pone.0153574 27078885.
77. Mathur D, López-Rodas G, Casanova B, Marti MB. Perturbed Glucose Metabolism: Insights into Multiple Sclerosis Pathogenesis. Frontiers in Neurology. 2014;5(250). doi: 10.3389/fneur.2014.00250 25520698
78. Nguyen TT, Oh SS, Weaver D, Lewandowska A, Maxfield D, Schuler M-H, et al. Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proceedings of the National Academy of Sciences. 2014;111(35):E3631–E40. doi: 10.1073/pnas.1402449111 25136135
79. Koch MW, George S, Wall W, Wee Yong V, Metz LM. Serum NSE level and disability progression in multiple sclerosis. Journal of the neurological sciences. 2015;350(1–2):46–50. Epub 2015/02/18. doi: 10.1016/j.jns.2015.02.009 25686504.
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