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Disease Modeling and Therapeutic Strategies in CMT2A: State of the Art

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Abstract

Mitofusin 2 (MFN2) is a protein of the mitochondrial outer membrane that belongs to a family of highly conserved dynamin-related GTPases. It is implicated in several intracellular pathways; however, its main role is the regulation of mitochondrial dynamics, in particular mitochondrial fusion. Mutations in MFN2 are associated with Charcot–Marie–Tooth disease type 2A (CMT2A), a neurological disorder characterized by a wide spectrum of clinical features, primarily a motor sensory neuropathy. The cellular and molecular mechanisms by which MFN2 mutations lead to neuronal degeneration are largely unknown, and there is currently no cure for patients. Here, we present the most recent in vitro and in vivo models of CMT2A and the more promising therapeutic approaches under development. These models and therapies may represent relevant tools for the study and recovery of defective mitochondrial dynamics that seem to play a significant role in the pathogenesis of other more common neurodegenerative diseases.

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Abbreviations

CMT:

Charcot–Marie–Tooth disease

MCNV:

Motor nerve conduction velocity

MNs:

Motor neurons

SNs:

Sensory neurons

IPSCs:

Induced pluripotent stem cells

ASO:

Antisense oligonucleotide

RNAi:

RNA interference

CRISPR:

Clustered regularly interspersed short palindromic repeats

Cas9:

Caspase 9

KO:

Knockout

References

  1. Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E et al (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36(5):449–451

    Article  PubMed  Google Scholar 

  2. Stuppia G, Rizzo F, Riboldi G, Del Bo R, Nizzardo M, Simone C et al (2015) MFN2-related neuropathies: clinical features, molecular pathogenesis and therapeutic perspectives. J Neurol Sci 356(1–2):7–18. Available from: https://doi.org/10.1016/j.jns.2015.05.033

    Article  CAS  PubMed  Google Scholar 

  3. Braathen GJ, Sand JC, Lobato A, Høyer H, Russell MB (2011) Genetic epidemiology of Charcot-Marie-Tooth in the general population. Eur J Neurol 18(1):39–48

    Article  CAS  PubMed  Google Scholar 

  4. Barreto LCLS, Oliveira FS, Nunes PS, De França Costa IMP, Garcez CA, Goes GM et al (2016) Epidemiologic study of Charcot-Marie-Tooth disease: a systematic review. Neuroepidemiology 46(3):157–165

    Article  PubMed  Google Scholar 

  5. Bergamin G, Boaretto F, Briani C, Pegoraro E, Cacciavillani M, Martinuzzi A, Muglia M, Vettori A et al (2014) Mutation analysis of MFN2, GJB1, MPZ and PMP22 in Italian patients with axonal Charcot-Marie-Tooth disease. NeuroMolecular Med 16(3):540–550

    Article  CAS  PubMed  Google Scholar 

  6. Verhoeven K, Claeys KG, Züchner S, Schröder JM, Weis J, Ceuterick C et al (2006) MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 129(8):2093–2102

    Article  PubMed  Google Scholar 

  7. Feely SME, Laura M, Siskind CE, Sottile S, Davis M, Gibbons VS, Reilly MM, Shy ME (2011) MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology 76(20):1690–1696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Piscosquito G, Saveri P, Magri S, Ciano C, Di Bella D, Milani M et al (2015) Mutational mechanisms in MFN2 -related neuropathy: compound heterozygosity for recessive and semidominant mutations. J Peripher Nerv Syst 20(4):380–386

    Article  CAS  PubMed  Google Scholar 

  9. Nicholson GA, Magdelaine C, Zhu D, Grew S, Ryan MM, Sturtz F, Vallat JM, Ouvrier RA (2008) Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations. Neurology 70:1678–1681

    Article  CAS  PubMed  Google Scholar 

  10. Polke JM, Laura M, Pareyson D, Taroni F, Milani M, Bergamin G, Gibbons VS, Houlden H et al (2011) Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations. Neurology 77:168–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tan CA, Rabideau M, Blevins A, Westbrook MJ, Ekstein T, Nykamp K, Deucher A, Harper A et al (2016) Autosomal recessive MFN2-related Charcot-Marie-Tooth disease with diaphragmatic weakness: case report and literature review. Am J Med Genet 170(6):1580–1584

    Article  CAS  PubMed  Google Scholar 

  12. Zhu D, Kennerson ML, Walizada G, Vance JM, Nicholson GA (2005) Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology 65:496–497

    Article  CAS  PubMed  Google Scholar 

  13. Züchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S et al (2006) Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 59(2):276–281

    Article  PubMed  Google Scholar 

  14. Filadi R, Pendin D, Pizzo P (2018) Mitofusin 2: from functions to disease. Cell Death Dis 9(3). Available from: https://doi.org/10.1038/s41419-017-0023-6

  15. Chandhok G, Lazarou M, Neumann B (2017) Structure, function, and regulation of mitofusin-2 in health and disease. Biol Rev 61

  16. El Fissi N, Rojo M, Aouane A, Karatas E, Poliacikova G, David C, Royet J, Rival T (2018) Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy. EMBO Rep 19:e45241. Available from: https://doi.org/10.15252/embr.201745241

  17. Bombelli F, Stojkovic T, Dubourg O, Echaniz-Laguna A, Tardieu S, Larcher K, Amati-Bonneau P, Latour P et al (2014) Charcot-Marie-Tooth disease type 2A from typical to rare phenotypic and genotypic features. JAMA Neurol 71:1036–1042

    Article  PubMed  Google Scholar 

  18. Lawson VH, Graham BV, Flanigan KM (2005) Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 65(2):197–204

    Article  CAS  PubMed  Google Scholar 

  19. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676

    Article  CAS  PubMed  Google Scholar 

  20. Saporta MA, Dang V, Volfson D, Zou B, Xie XS, Adebola A et al (2015) Axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties. Exp Neurol 263:190–199

    Article  CAS  PubMed  Google Scholar 

  21. Rizzo F, Ronchi D, Salani S, Nizzardo M, Fortunato F, Bordoni A, Stuppia G, del Bo R et al (2016) Selective mitochondrial depletion, apoptosis resistance, and increased mitophagy in human Charcot-Marie-Tooth 2A motor neurons. Hum Mol Genet 25(19):4266–4281

    Article  CAS  PubMed  Google Scholar 

  22. Cartoni R, Arnaud E, Médard JJ, Poirot O, Courvoisier DS, Chrast R, Martinou JC (2010) Expression of mitofusin 2R94Q in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A. Brain. 133(5):1460–1469

    Article  PubMed  Google Scholar 

  23. Bannerman P, Burns T, Xu J, Miers L, Pleasure D (2016) Mice hemizygous for a pathogenic mitofusin- 2 allele exhibit hind limb/foot gait deficits and phenotypic perturbations in nerve and muscle. PLoS One 11(12):17–22

    Article  Google Scholar 

  24. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160(2):189–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH (2010) Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci 30(12):4232–4240. Available from: https://doi.org/10.1523/JNEUROSCI.6248-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Misko AL, Sasaki Y, Tuck E, Milbrandt J, Baloh RH (2012) Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration. J Neurosci 32(12):4145–4155. Available from: https://doi.org/10.1523/JNEUROSCI.6338-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bhandari P, Song M, Chen Y, Burelle Y, Dorn GW II (2014) Mitochondrial contagion induced by parkin deficiency in drosophila hearts and its containment by suppressing mitofusin. Circulation Research 114(2):257–265. Available from: https://doi.org/10.1161/CIRCRESAHA.114.302734

  28. Vettori A, Bergamin G, Moro E, Vazza G, Polo G, Tiso N, Argenton F, Mostacciuolo ML (2011) Developmental defects and neuromuscular alterations due to mitofusin 2 gene (MFN2) silencing in zebrafish: a new model for Charcot-Marie-Tooth type 2A neuropathy. Neuromuscul Disord 21(1):58–67. Available from: https://doi.org/10.1016/j.nmd.2010.09.002

    Article  PubMed  Google Scholar 

  29. Chapman AL, Bennett EJ, Ramesh TM, De Vos KJ, Grierson AJ (2013) Axonal transport defects in a mitofusin 2 loss of function model of Charcot-Marie-Tooth disease in zebrafish. PLoS One 8(6)

  30. Pareyson D, Saveri P, Pisciotta C (2017) New developments in Charcot–Marie–Tooth neuropathy and related diseases. Curr Opin Neurol 30:471–480

    Article  CAS  PubMed  Google Scholar 

  31. Eldridge CF, Bunge MB, Bunge RP (1989) Differentiation of axon-related Schwann cells in vitro: II. Control of myelin formation by basal lamina. J Neurosci 9(2):625–638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gess B, Baets J, De Jonghe P, Reilly MM, Pareyson D, Young P (2015) Ascorbic acid for the treatment of Charcot-Marie-Tooth disease ( review ). Cochrane Database Syst Rev (12)

  33. Sereda MW, Meyer Zu Hörste G, Suter U, Uzma N, Nave KA (2003) Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med 9(12):1533–1537

    Article  CAS  PubMed  Google Scholar 

  34. Chahbouni M, Lòpez MS, Molina-Carballo A, Haro D, Muñoz-Hoyos A, Fernàndez-Ortis M, Guerra-Librero A, Acuna-Castroviejo D (2017) Melatonin treatment reduces oxidative damage and normalizes plasma pro-inflammatory cytokines in patients suffering from Charcot-Marie-Tooth neuropathy: a pilot study in three children. Molecules 22(1728):1-14. Available from: https://doi.org/10.3390/molecules22101728

  35. Smith CA, Chetlin RD, Gutmann L, Yeater RA, Alway SE (2006) Effects of exercise and creatine on myosin heavy chain isoform composition in patients with Charcot-Marie-Tooth disease. Muscle Nerve 34(5):586–594

    Article  CAS  PubMed  Google Scholar 

  36. Franco A, Kitsis RN, Fleischer JA, Gavathiotis E, Kornfeld OS, Gong G, Biris N, Benz A et al (2016) Correcting mitochondrial fusion by manipulating mitofusin conformations. Nature 540(7631):74–79. Available from: https://doi.org/10.1038/nature20156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rocha AG, Franco A, Krezel AM, Rumsey JM, Alberti JM, Knight WC et al (2018) MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A. Science (80- ) 360(6386):336–341

    Article  CAS  Google Scholar 

  38. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW et al (2017) Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377(18):1713–1722. Available from: https://doi.org/10.1056/NEJMoa1706198

    Article  CAS  PubMed  Google Scholar 

  39. Xu GX, Zhou H, Zhou S, Yu Y, Wu R, Xu Z (2005) An RNAi strategy for treatment of amyotrophic lateral sclerosis caused by mutant Cu,Zn superoxide dismutase. J Neurochem 92(2):362–367

    Article  PubMed  Google Scholar 

  40. Rinaldi C, Wood MJA (2017) Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. Available from: https://doi.org/10.1038/nrneurol.2017.148.

  41. Herrmann DN (2008) Experimental therapeutics in hereditary neuropathies: the past, the present, and the future. Neurotherapeutics. 5(4):507–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hoy SM (2017) Nusinersen: first global approval. Drugs. 77(4):473–479

    Article  CAS  PubMed  Google Scholar 

  43. Voelker R (2016) First DMD drug gains approval. JAMA 316(17):1756

  44. Deng Y, Wang CC, Choy KW, Du Q, Chen J, Wang Q et al (2014) Therapeutic potentials of gene silencing by RNA interference: principles, challenges, and new strategies. Gene 538(2):217–227

    Article  CAS  PubMed  Google Scholar 

  45. Aagaard L, Rossi JJ (2007) RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev 59(2–3):75–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lam JKW, Chow MYT, Zhang Y, Leung SWS (2015) siRNA versus miRNA as therapeutics for gene silencing. Mol Ther - Nucleic Acids 4(9):1–20

    Google Scholar 

  47. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339(6121):819-823. Available from: https://doi.org/10.1126/science.1231143

  48. Zhan T, Rindtorff N, Betge J, Ebert MP, Boutros M (2018) CRISPR/Cas9 for cancer research and therapy. Semin Cancer Biol. Available from: https://doi.org/10.1016/j.semcancer.2018.04.001

  49. Zhang XH, Tee LY, Wang XG, Huang QS, Yang SH (2015) Off-target effects in CRISPR/Cas9-mediated genome engineering. Mol Ther - Nucleic Acids 4(11):e264. Available from: https://doi.org/10.1038/mtna.2015.37

  50. Liao HK, Hatanaka F, Araoka T, Reddy P, Wu MZ, Sui Y et al (2017) In vivo target gene activation via CRISPR/Cas9-mediated trans-epigenetic modulation. Cell 171(7):1495–1507.e15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Baylis F, McLeod M (2017) First-in-human phase 1 CRISPR gene editing cancer trials: are we ready? Curr Gene Ther 17:309–319. Available from: https://doi.org/10.2174/1566523217666171121165935

  52. Joshi CR, Labhasetwar V, Ghorpade A (2017) Destination brain: The past, present, and future of therapeutic gene delivery. J NeuroImmune Pharmacol 12(1):51–83

    Article  PubMed  PubMed Central  Google Scholar 

  53. DeVos SL, Miller T (2013) Direct intraventricular delivery of drugs to the rodent central nervous system. J Vis Exp.75:e50326. Available from: https://doi.org/10.3791/50326

  54. Weinberg MS, Samulski RJ, McCown TJ (2013) Adeno-associated virus (AAV) gene therapy for neurological disease. Neuropharmacology 69:82–88. Available from: https://doi.org/10.1016/j.neuropharm.2012.03.004

    Article  CAS  PubMed  Google Scholar 

  55. Klein RL, Dayton RD, Leidenheimer NJ, Jansen K, Golde TE, Zweig RM (2006) Efficient neuronal gene transfer with AAV8 leads to neurotoxic levels of tau or green fluorescent proteins. Mol Ther 13(3):517–527. Available from: https://doi.org/10.1016/j.ymthe.2005.10.008

    Article  CAS  PubMed  Google Scholar 

  56. Markakis EA, Vives KP, Bober J, Leichtle S, Leranth C, Beecham J, Elsworth JD, Roth RH et al (2010) Comparative transduction efficiency of AAV vector serotypes 1-6 in the substantia nigra and striatum of the primate brain. Mol Ther 18(3):588–593. Available from: https://doi.org/10.1038/mt.2009.286

    Article  CAS  PubMed  Google Scholar 

  57. Hadaczek P, Forsayeth J, Mirek H, Munson K, Bringas J, Pivirotto P, McBride JL, Davidson BL, Bankiewicz KS (2009) Transduction of nonhuman primate brain with adeno-associated virus serotype 1: vector trafficking and immune response. Hum Gene Ther 20:225–237

  58. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK (2009) Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 27(1):59–65

    Article  CAS  PubMed  Google Scholar 

  59. Foust KD, Salazar DL, Likhite S, Ferraiuolo L, Ditsworth D, Ilieva H, Meyer K, Schmelzer L, Braun L, Cleveland DW, Kaspar BK (2013) Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Molecular Therapy 21(12):2148–2159. Available from: https://doi.org/10.1038/mt.2013.211

  60. Meyer K, Ferraiuolo L, Schmelzer L, Braun L, Mcgovern V, Likhite S et al (2015) Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose–response study in mice and nonhuman primates. Mol Ther 23(3):477–487. Available from: https://doi.org/10.1038/mt.2014.210

    Article  CAS  PubMed  Google Scholar 

  61. Miyanohara A, Kamizato K, Juhas S, Juhasova J, Navarro M, Marsala S et al (2016) Potent spinal parenchymal AAV9-mediated gene delivery by subpial injection in adult rats and pigs. Mol Ther - Methods Clin Dev 3:16046. Available from: https://doi.org/10.1038/mtm.2016.46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ameri H (2018) Prospect of retinal gene therapy following commercialization of voretigene neparvovec-rzyl for retinal dystrophy mediated by RPE65 mutation. J Curr Ophthalmol 30(1):1–2. Available from: https://doi.org/10.1016/j.joco.2018.01.006

    Article  PubMed  PubMed Central  Google Scholar 

  63. Nizzardo M, Simone C, Rizzo F, Salani S, Dametti S, Rinchetti P et al (2015) Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model. Sci Adv 1(2):1–10

    Article  Google Scholar 

  64. Johnson-Kerner BL, Roth L, Greene JP, Wichterle H, Sproule DM (2014) Giant axonal neuropathy: An updated perspective on its pathology and pathogenesis. Muscle Nerve 50(4):467–476

    Article  CAS  PubMed  Google Scholar 

  65. Sahenk Z, Nagaraja HN, McCracken BS, King WM, Freimer ML, Cedarbaum JM et al (2005) NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients. Neurology. 65(5):681–689

    Article  CAS  PubMed  Google Scholar 

  66. Flax JD, Aurora S, Yang C, Simonin C, Wills AM, Billinghurst LL, Jendoubi M, Sidman RL et al (1998) Engraftable human neural stem cells respond to development cues, replace neurons, and express foreign genes. Nat Biotechnol 16(11):1033–1039

    Article  CAS  PubMed  Google Scholar 

  67. Corti S, Locatelli F, Papadimitriou D, Donadoni C, Del Bo R, Crimi M et al (2006) Transplanted ALDHhiSSCloneural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1. Hum Mol Genet 15(2):167–187

    Article  CAS  PubMed  Google Scholar 

  68. Nizzardo M, Bucchia M, Ramirez A, Trombetta E, Bresolin N, Comi GP et al (2015) iPSC-derived LewisX+CXCR4+β1-integrin+ neural stem cells improve the amyotrophic lateral sclerosis phenotype by preserving motor neurons and muscle innervation in human and rodent models. Hum Mol Genet 25(15):3152–3163

    Article  Google Scholar 

  69. Yang YM, Gupta SK, Kim KJ, Powers BE, Cerqueira A, Wainger BJ, Ngo HD, Rosowski KA et al (2013) A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Cell Stem Cell 12(6):713–726. Available from: https://doi.org/10.1016/j.stem.2013.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Simone C, Nizzardo M, Rizzo F, Ruggieri M, Riboldi G, Salani S, Bucchia M, Bresolin N et al (2014) IPSC-derived neural stem cells act via kinase inhibition to exert neuroprotective effects in spinal muscular atrophy with respiratory distress type 1. Stem Cell Reports 3(2):297–311. Available from: https://doi.org/10.1016/j.stemcr.2014.06.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Leal A, Ichim TE, Marleau AM, Lara F, Kaushal S, Riordan NH (2008) Immune effects of mesenchymal stem cells: Implications for Charcot-Marie-Tooth disease. Cell Immunol 253(1–2):11–15

    Article  CAS  PubMed  Google Scholar 

  72. Kimbrel EA, Lanza R (2015) Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat Rev Drug Discov 14(10):681–692. Available from: https://doi.org/10.1038/nrd4738

    Article  CAS  PubMed  Google Scholar 

  73. Shi Y, Inoue H, Wu JC, Yamanaka S (2017) Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 16(2):115–130. Available from: https://doi.org/10.1038/nrd.2016.245

    Article  CAS  PubMed  Google Scholar 

  74. Murphy SM, Herrmann DN, McDermott MP, Scherer SS, Shy ME, Reilly MM et al (2011) Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease. J Peripher Nerv Syst 16(3):191–198

    Article  PubMed  PubMed Central  Google Scholar 

  75. Cornett KMD, Menezes MP, Shy RR, Moroni I, Pagliano E, Pareyson D, Estilow T, Yum SW et al (2017) Natural history of Charcot-Marie-Tooth disease during childhood. Ann Neurol 82(3):353–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fledrich R, Mannil M, Leha A, Ehbrecht C, Solari A, Pelayo-Negro AL, Berciano J, Schlotter-Weigel B et al (2017) Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A. J Neurol Neurosurg Psychiatry 88(11):941–952

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Associazione Progetto Mitofusina 2 Onlus and Associazione Amici del Centro Dino Ferrari for their support.

Funding

This study is supported by grant “Ricerca Corrente 2019: Analisi dei pathway molecolari condivisi coinvolti nella patogenesi delle malattie neurodegenerative mediante modelli in vitro basati su cellule staminali” from the Italian Ministry of Health.

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Authors and Affiliations

  1. Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy

    Kordelia Barbullushi, Elena Abati, Federica Rizzo, Nereo Bresolin, Giacomo P. Comi & Stefania Corti

  2. Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Via Francesco Sforza 35, 20122, Milan, Italy

    Nereo Bresolin, Giacomo P. Comi & Stefania Corti

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  1. Kordelia Barbullushi
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  2. Elena Abati
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  3. Federica Rizzo
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Correspondence to Stefania Corti.

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Barbullushi, K., Abati, E., Rizzo, F. et al. Disease Modeling and Therapeutic Strategies in CMT2A: State of the Art. Mol Neurobiol 56, 6460–6471 (2019). https://doi.org/10.1007/s12035-019-1533-2

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