MFN2-related neuropathies: Clinical features, molecular pathogenesis and therapeutic perspectives

Journal of the Neurological Sciences

Volumn 356, Issue 1-2, 2015, Pages 7-18

  Stuppia, Giulia ^a   Rizzo, Federica ^a   Riboldi, Giulietta ^a   Del Bo, Roberto ^a   Nizzardo, Monica ^a   Simone, Chiara ^a   Comi, Giacomo P ^a   Bresolin, Nereo ^a   Corti, Stefania ^a  

^a UNIVERSITY OF MILAN   (Italy)

Author keywords

Charcot Marie Tooth disease type 2A; Clinical and genetic features; Mitochondrial network; Mitofusin 2; Neurodegeneration; Pathogenetic mechanisms

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; COPPER ZINC SUPEROXIDE DISMUTASE; CYTOCHROME C; DNA; KINESIN 1; MITOCHONDRIAL DNA; MITOFUSIN 1; MITOFUSIN 2; MYOCYTE ENHANCER FACTOR 2; PARKIN; PROTEIN P62; REACTIVE OXYGEN METABOLITE; TAR DNA BINDING PROTEIN; GUANOSINE TRIPHOSPHATASE; MFN2 PROTEIN, HUMAN; MITOCHONDRIAL PROTEIN;

ARTICLE; BABINSKI REFLEX; CELL RESPIRATION; CENTRAL SCOTOMA; CHARCOT MARIE TOOTH DISEASE TYPE 2A; CHOREA; CLINICAL FEATURE; COLOR VISION DEFECT; CONSCIOUSNESS DISORDER; DEGENERATIVE DISEASE; DISEASE COURSE; DYSAUTONOMIA; EVOKED VISUAL RESPONSE; FOOT MALFORMATION; GENE MUTATION; GENETIC ASSOCIATION; HAND TREMOR; HEARING IMPAIRMENT; HEREDITARY MOTOR SENSORY NEUROPATHY; HUMAN; MISSENSE MUTATION; MITOCHONDRIAL DYNAMICS; MITOCHONDRIAL VOLUME; MITOPHAGY; MOLECULAR PATHOLOGY; NERVE DEGENERATION; NERVE FIBER TRANSPORT; NEUROPATHY; NONSENSE MUTATION; NYSTAGMUS; OCCUPATIONAL THERAPY; ONSET AGE; OPTIC NERVE ATROPHY; PARESIS; PERCEPTION DEAFNESS; PHENOTYPE; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; SCOLIOSIS; SKELETON MALFORMATION; SYSTEMATIC REVIEW; VIBRATION SENSE; VISUAL ACUITY; VOCAL CORD PARALYSIS; VOMITING; WEAKNESS; ANIMAL; CHARCOT-MARIE-TOOTH DISEASE; GENETICS; METABOLISM; MITOCHONDRION; MUTATION; NERVE CELL; PATHOLOGY;

ANIMALS; CHARCOT-MARIE-TOOTH DISEASE; GTP PHOSPHOHYDROLASES; HUMANS; MITOCHONDRIA; MITOCHONDRIAL PROTEINS; MUTATION; NEURONS; PHENOTYPE;

EID: 84939262128     PISSN: 0022510X     EISSN: 18785883     Source Type: Journal    
DOI: 10.1016/j.jns.2015.05.033     Document Type: Review

References (119)

1. M. Ranieri, S. Brajkovic, G. Riboldi, D. Ronchi, F. Rizzo, N. Bresolin, S. Corti, and G.P. Comi Mitochondrial fusion proteins and human diseases Neurol. Res. Int. 2013 2013 2938 2993
2. A.R. van Vliet, T. Verfaillie, and P. Agostinis New functions of mitochondria associated membranes in cellular signaling Biochim. Biophys. Acta 2014 1843 2253 2262
3. E.A. Schon, and S. Przedborski Mitochondria: the next (neurode)generation Neuron 70 2011 1033 1053
4. D.A. Berthold, and J.N. Siedow Partial purification of the cyanide-resistant alternative oxidase of skunk cabbage (Symplocarpus foetidus) mitochondria Plant Physiol. 101 1993 113 119
5. C. Fischer, S. Trajanoski, L. Papić, C. Windpassinger, G. Bernert, M. Freilinger, M. Schabhüttl, M. Arslan-Kirchner, P. Javaher-Haghighi, B. Plecko, J. Senderek, C. Rauscher, W.N. Löscher, T.R. Pieber, A.R. Janecke, and M. Auer-Grumbach SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease J. Neurol. 259 2012 515 523
6. H. Chen, and D.C. Chan Critical dependence of neurons on mitochondrial dynamics Curr. Opin. Cell Biol. 18 2006 453 459
7. D. Pathak, A. Berthet, and K. Nakamura Energy failure: does it contribute to neurodegeneration? Ann. Neurol. 74 2013 506 516
8. L. Dupuis Mitochondrial quality control in neurodegenerative diseases Biochimie 100 2014 177 183
9. F. Burté, V. Carelli, P.F. Chinnery, and P. Yu-Wai-Man Disturbed mitochondrial dynamics and neurodegenerative disorders Nat. Rev. Neurol. 11 2015 11 24
10. J.E. Duncan, and L.S. Goldstein The genetics of axonal transport and axonal transport disorders PLoS Genet. 2 2006 e124
11. K.J. De Vos, A.J. Grierson, S. Ackerley, and C.C. Miller Role of axonal transport in neurodegenerative diseases Annu. Rev. Neurosci. 31 2008 151 173
12. W. Wang, L. Li, W.L. Lin, D.W. Dickson, L. Petrucelli, T. Zhang, and X. Wang The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons Hum. Mol. Genet. 22 2013 4706 4719
13. K. Itoh, K. Nakamura, M. Iijima, and H. Sesaki Mitochondrial dynamics in neurodegeneration Trends Cell Biol. 23 2013 64 71
14. S.A. Detmer, and D.C. Chan Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations J. Cell Biol. 176 2007 405 414
15. R.H. Baloh Mitochondrial dynamics and peripheral neuropathy Neuroscientist 14 2008 12 18
16. S. Vielhaber, G. Debska-Vielhaber, V. Peeva, S. Schoeler, A.P. Kudin, I. Minin, S. Schreiber, R. Dengler, K. Kollewe, W. Zuschratter, C. Kornblum, G. Zsurka, and W.S. Kunz Mitofusin 2 mutations affect mitochondrial function by mitochondrial DNA depletion Acta Neuropathol. 125 2013 245 256
17. J.M. Vallat, R.A. Ouvrier, J.D. Pollard, C. Magdelaine, D. Zhu, G.A. Nicholson, S. Grew, M.M. Ryan, and B. Funalot Histopathological findings in hereditary motor and sensory neuropathy of axonal type with onset in early childhood associated with mitofusin 2 mutations J. Neuropathol. Exp. Neurol. 67 2008 1097 1102
18. S. Züchner, P. De Jonghe, A. Jordanova, K.G. Claeys, V. Guergueltcheva, S. Cherninkova, S.R. Hamilton, G. Van Stavern, K.M. Krajewski, J. Stajich, I. Tournev, K. Verhoeven, C.T. Langerhorst, M. de Visser, F. Baas, T. Bird, V. Timmerman, M. Shy, and J.M. Vance Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2 Ann. Neurol. 59 2006 276 281
19. S.Y. Park, S.Y. Kim, Y.H. Hong, S.I. Cho, M.W. Seong, and S.S. Park A novel double mutation in cis in MFN2 causes Charcot-Marie-Tooth neuropathy type 2A Neurogenetics. 13 2012 275 280
20. F. Gemignani, G. Melli, S. Alfieri, C. Inglese, and A. Marbini Sensory manifestations in Charcot-Marie-Tooth disease J. Peripher. Nerv. Syst. 9 2004 7 14
21. E.L. Neves, and F. Kok Clinical and neurophysiological investigation of a large family with dominant Charcot-Marie-Tooth type 2 disease with pyramidal signs Arq. Neuropsiquiatr. 69 2011 424 430
22. F. Gemignani, and A. Marbini Charcot-Marie-Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2 J. Neurol. Sci. 184 2001 1 9
23. A.A. Gabreëls-Festen, E.M. Joosten, F.J. Gabreëls, F.G. Jennekens, R.H. Gooskens, and D.F. Stegeman Hereditary motor and sensory neuropathy of neuronal type with onset in early childhood Brain 114 1991 1855 1870
24. M. Muglia, M. Zappia, V. Timmerman, P. Valentino, A.L. Gabriele, F.L. Conforti, P. De Jonghe, M. Ragno, R. Mazzei, M. Sabatelli, G. Nicoletti, A.M. Patitucci, R.L. Oliveri, F. Bono, A. Gambardella, and A. Quattrone Clinical and genetic study of a large Charcot-Marie-Tooth type 2A family from southern Italy Neurology 56 2001 100 103
25. M. Saito, Y. Hayashi, T. Suzuki, H. Tanaka, I. Hozumi, and S. Tsuji Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2A Neurology 49 1997 1630 1635
26. K. Verhoeven, K.G. Claeys, S. Züchner, J.M. Schröder, J. Weis, C. Ceuterick, A. Jordanova, E. Nelis, E. De Vriendt, M. Van Hul, P. Seeman, R. Mazanec, G.M. Saifi, K. Szigeti, P. Mancias, I.J. Butler, A. Kochanski, B. Ryniewicz, J. De Bleecker, P. Van den Bergh, C. Verellen, R. Van Coster, N. Goemans, M. Auer-Grumbach, W. Robberecht, V. Milic Rasic, Y. Nevo, I. Tournev, V. Guergueltcheva, F. Roelens, P. Vieregge, P. Vinci, M.T. Moreno, H.J. Christen, M.E. Shy, J.R. Lupski, J.M. Vance, P. De Jonghe, and V. Timmerman MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2 Brain 129 2006 2093 2102
27. G. Sole, X. Ferrer, C. Vital, M.L. Martin-Negrier, A. Vital, and P. Latour Ultrastructural mitochondrial modifications characteristic of mitofusin 2 mutations (CMT2A) J. Peripher. Nerv. Syst. 14 2009 206 207
28. S. Vucic, M. Kennerson, D. Zhu, E. Miedema, C. Kok, and G.A. Nicholson CMT with pyramidal features. Charcot-Marie-Tooth Neurology 60 2003 696 699
29. K.W. Chung, S.B. Kim, K.D. Park, K.G. Choi, J.H. Lee, H.W. Eun, J.S. Suh, J.H. Hwang, W.K. Kim, B.C. Seo, S.H. Kim, I.H. Son, S.M. Kim, I.N. Sunwoo, and B.O. Choi Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations Brain 129 2006 2103 2118
30. S. Züchner, and J.M. Vance Molecular genetics of autosomal-dominant axonal Charcot-Marie-Tooth disease Neruomol. Med. 8 2006 63 74
31. K. Brockmann, S. Dreha-Kulaczewski, P. Dechent, C. Bönnemann, G. Helms, M. Kyllerman, W. Brück, J. Frahm, K. Huehne, J. Gärtner, and B. Rautenstrauss Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations J. Neurol. 255 2008 1049 1058
32. F. Boaretto, A. Vettori, A. Casarin, G. Vazza, M. Muglia, M.G. Rossetto, T. Cavallaro, N. Rizzuto, V. Carelli, L. Salviati, M.L. Mostacciuolo, and A. Martinuzzi Severe CMT type 2 with fatal encephalopathy associated with a novel MFN2 splicing mutation Neurology 74 2010 1919 1921
33. G.A. Nicholson, C. Magdelaine, D. Zhu, S. Grew, M.M. Ryan, F. Sturtz, J.M. Vallat, and R.A. Ouvrier Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations Neurology 70 2008 1678 1681
34. M. Luigetti, G.M. Fabrizi, F. Taioli, A. Conte, A. Del Grande, and M. Sabatelli Clinical, electrophysiological and pathological findings of a patient with CMT2 due to the p.Ala738Val mitofusin 2 mutation J. Neurol. Sci. 307 2011 168 170
35. F. Bombelli, T. Stojkovic, O. Dubourg, A. Echaniz-Laguna, S. Tardieu, K. Larcher, P. Amati-Bonneau, P. Latour, O. Vignal, C. Cazeneuve, A. Brice, and E. Leguern Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features JAMA Neurol. 71 2014 1036 1042
36. R.M. Chalmers, A.C. Bird, and A.E. Harding Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy J. Neurol. Neurosurg. Psychiatry 60 1996 195 196
37. S. Züchner, I.V. Mersiyanova, M. Muglia, N. Bissar-Tadmouri, J. Rochelle, E.L. Dadali, M. Zappia, E. Nelis, A. Patitucci, J. Senderek, Y. Parman, O. Evgrafov, P.D. Jonghe, Y. Takahashi, S. Tsuji, M.A. Pericak-Vance, A. Quattrone, E. Battaloglu, A.V. Polyakov, V. Timmerman, J.M. Schröder, and J.M. Vance Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A Nat. Genet. 36 2004 449 451
38. G. Bergamin, C. Dalla Torre, M. Cacciavillani, M. Lucchetta, F. Boaretto, M. Campagnolo, M.L. Mostacciuolo, and C. Briani Novel mutation of the mitofusin 2 gene in a family with Charcot-Marie-Tooth disease type 2 Muscle Nerve 49 2014 145 146
39. H.J. Cho, D.H. Sung, B.J. Kim, and C.S. Ki Mitochondrial GTPase mitofusin 2 mutations in Korean patients with Charcot-Marie-Tooth neuropathy type 2 Clin. Genet. 71 2007 267 272
40. K. Kijima, C. Numakura, H. Izumino, K. Umetsu, A. Nezu, T. Shiiki, M. Ogawa, Y. Ishizaki, T. Kitamura, Y. Shozawa, and K. Hayasaka Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A Hum. Genet. 116 2005 23 27
41. C. Neusch, J. Senderek, T. Eggermann, E. Elolff, M. Bähr, and C. Schneider-Gold Mitofusin 2 gene mutation (R94Q) causing severe early-onset axonal polyneuropathy (CMT2A) Eur. J. Neurol. 14 2007 575 577
42. J. Calvo, B. Funalot, R.A. Ouvrier, L. Lazaro, A. Toutain, P. De Mas, P. Bouche, B. Gilbert-Dussardier, M.C. Arne-Bes, J.P. Carrière, H. Journel, M.C. Minot-Myhie, C. Guillou, K. Ghorab, L. Magy, F. Sturtz, J.M. Vallat, and C. Magdelaine Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations Arch. Neurol. 66 2009 1511 1516
43. J.M. Polke, M. Laurá, D. Pareyson, F. Taroni, M. Milani, G. Bergamin, V.S. Gibbons, H. Houlden, S.C. Chamley, J. Blake, C. Devile, R. Sandford, M.G. Sweeney, M.B. Davis, and M.M. Reilly Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations Neurology 77 2011 168 173
44. V.H. Lawson, B.V. Graham, and K.M. Flanigan Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene Neurology 65 2005 197 204
45. O.M. de Brito, and L. Scorrano Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion Antioxid. Redox Signal. 10 2008 621 633
46. H. Chen, and D.C. Chan Emerging functions of mammalian mitochondrial fusion and fission Hum. Mol. Genet. 14 2005 283 289
47. H. Chen, S.A. Detmer, A.J. Ewald, E.E. Griffin, S.E. Fraser, and D.C. Chan Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development J. Cell Biol. 160 2003 189 200
48. F. Haun, T. Nakamura, and S.A. Lipton Dysfunctional mitochondrial dynamics in the pathophysiology of neurodegenerative diseases J. Cell Death 6 2013 27 35
49. T. Koshiba, S.A. Detmer, J.T. Kaiser, H. Chen, J.M. McBride, and D.C. Chan Structural basis of mitochondrial tethering by mitofusin complexes Science 305 2004 858 862
50. M. Neuspiel, R. Zunino, S. Gangaraju, P. Rippstein, and H. McBride Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization J. Biol. Chem. 280 2005 25060 25070
51. A. Misko, S. Jiang, I. Wegorzewska, J. Milbrandt, and R.H. Baloh Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex J. Neurosci. 30 2010 4232 4240
52. A.B. Knott, and E. Bossy-Wetzel Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration Ann. N. Y. Acad. Sci. 1147 2008 283 292
53. Z.H. Sheng Mitochondrial trafficking and anchoring in neurons: new insight and implications J. Cell Biol. 204 2014 1087 1098
54. M. Milone, and E.E. Benarroch Mitochondrial dynamics: general concepts and clinical implications Neurology 78 2012 1612 1619
55. J.S. Kang, J.H. Tian, P.Y. Pan, P. Zald, C. Li, C. Deng, and Z.H. Sheng Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation Cell 132 2008 137 148
56. Y.M. Chen, C. Gerwin, and Z.H. Sheng Dynein light chain LC8 regulates syntaphilin-mediated mitochondrial docking in axons J. Neurosci. 29 2009 9429 9438
57. O.S. Koutsopoulos, D. Laine, L. Osellame, D.M. Chudakov, R.G. Parton, A.E. Frazier, and M.T. Ryan Human Miltons associate with mitochondria and induce microtubule-dependent remodeling of mitochondrial networks Biochim. Biophys. Acta 1803 2010 564 574
58. K.E. Miller, and M.P. Sheetz Axonal mitochondrial transport and potential are correlated J. Cell Sci. 117 2004 2791 2804
59. M. Saotome, D. Safiulina, G. Szabadkai, S. Das, A. Fransson, P. Aspenstrom, R. Rizzuto, and G. Hajnóczky Bidirectional Ca2 + -dependent control of mitochondrial dynamics by the Miro GTPase Proc. Natl. Acad. Sci. U. S. A. 105 2008 20728 20733
60. R.H. Baloh, R.E. Schmidt, A. Pestronk, and J. Milbrandt Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations J. Neurosci. 27 2007 422 430
61. M.L. Tradewell, H.D. Durham, W.E. Mushynski, and B.J. Gentil Mitochondrial and axonal abnormalities precede disruption of the neurofilament network in a model of Charcot-Marie-Tooth disease type 2E and are prevented by heat shock proteins in a mutant-specific fashion J. Neuropathol. Exp. Neurol. 68 2009 642 652
62. A.L. Misko, Y. Sasaki, E. Tuck, J. Milbrandt, and R.H. Baloh Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration J. Neurosci. 32 2012 4145 4155
63. H. Chen, and D.C. Chan Mitochondrial dynamics - fusion, fission, movement, and mitophagy - in neurodegenerative diseases Hum. Mol. Genet. 18 2009 169 176
64. B.R. Webster, I. Scott, J. Traba, K. Han, and M.N. Sack Regulation of autophagy and mitophagy by nutrient availability and acetylation Biochim. Biophys. Acta 2014 1841 525 534
65. A. Tanaka, M.M. Cleland, S. Xu, D.P. Narendra, D.F. Suen, M. Karbowski, and R.J. Youle Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin J. Cell Biol. 191 2010 1367 1380
66. M.E. Gegg, J.M. Cooper, K.Y. Chau, M. Rojo, A.H. Schapira, and J.W. Taanman Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy Hum. Mol. Genet. 19 2010 4861 4870
67. Y. Chen, and G.W. Dorn 2nd PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria Science 340 2013 471 475
68. R.A. Nixon, and D.S. Yang Autophagy and neuronal cell death in neurological disorders Cold Spring Harb. Perspect. Biol. 4 2012
69. S. Ghavami, S. Shojaei, B. Yeganeh, S.R. Ande, J.R. Jangamreddy, M. Mehrpour, J. Christoffersson, W. Chaabane, A.R. Moghadam, H.H. Kashani, M. Hashemi, A.A. Owji, and M.J. Łos Autophagy and apoptosis dysfunction in neurodegenerative disorders Prog. Neurobiol. 112 2014 24 49
70. T. Shutt, M. Geoffrion, R. Milne, and H.M. McBride The intracellular redox state is a core determinant of mitochondrial fusion EMBO Rep. 13 2012 909 915
71. V. Rhein, X. Song, A. Wiesner, L.M. Ittner, G. Baysang, F. Meier, L. Ozmen, H. Bluethmann, S. Dröse, U. Brandt, E. Savaskan, C. Czech, J. Götz, and A. Eckert Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice Proc. Natl. Acad. Sci. U. S. A. 106 2009 20057 20062
72. S.S. Smaili, R.P. Ureshino, L. Rodrigues, K.K. Rocha, J.T. Carvalho, K.T. Oseki, C. Bincoletto, G.S. Lopes, and H. Hirata The role of mitochondrial function in glutamate-dependent metabolism in neuronal cells Curr. Pharm. Des. 17 2011 3865 3877
73. M. Hashimoto, E. Rockenstein, L. Crews, and E. Masliah Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases Neruomol. Med. 4 2003 21 36
74. D. Narendra, A. Tanaka, D.F. Suen, and R.J. Youle Parkin is recruited selectively to impaired mitochondria and promotes their autophagy J. Cell Biol. 183 2008 795 803
75. G. Krebiehl, S. Ruckerbauer, L.F. Burbulla, N. Kieper, B. Maurer, J. Waak, H. Wolburg, Z. Gizatullina, F.N. Gellerich, D. Woitalla, O. Riess, P.J. Kahle, T. Proikas-Cezanne, and R. Krüger Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1 PLoS One 5 2010 e9367
76. M. Lazarou, S.M. Jin, L.A. Kane, and R.J. Youle Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin Dev. Cell 22 2012 320 333
77. L. Li, X. Zhang, and W. Le Altered macroautophagy in the spinal cord of SOD1 mutant mice Autophagy 4 2008 290 293
78. S. Sasaki Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis J. Neuropathol. Exp. Neurol. 70 2011 349 359
79. M. Neumann, D.M. Sampathu, L.K. Kwong, A.C. Truax, M.C. Micsenyi, T.T. Chou, J. Bruce, T. Schuck, M. Grossman, C.M. Clark, L.F. McCluskey, B.L. Miller, E. Masliah, I.R. Mackenzie, H. Feldman, W. Feiden, H.A. Kretzschmar, J.Q. Trojanowski, and V.M. Lee Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science 314 2006 130 133
80. N.A. Reyes, J.K. Fisher, K. Austgen, S. VandenBerg, E.J. Huang, and S.A. Oakes Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis J. Clin. Invest. 120 2010 3673 3679
81. P. Shi, Y. Wei, J. Zhang, J. Gal, and H. Zhu Mitochondrial dysfunction is a converging point of multiple pathological pathways in amyotrophic lateral sclerosis J. Alzheimers Dis. 20 2010 S311 S324
82. A. Martorell-Riera, M. Segarra-Mondejar, J.P. Muñoz, V. Ginet, J. Olloquequi, J. Pérez-Clausell, M. Palacín, M. Reina, J. Puyal, A. Zorzano, and F.X. Soriano Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death EMBO J. 33 2014 2388 2407
83. W. Wang, F. Zhang, L. Li, F. Tang, S.L. Siedlak, H. Fujioka, Y. Liu, B. Su, Y. Pi, and X. Wang Mfn2 couples glutamate excitotoxicity and mitochondrial dysfunction in motor neurons J. Biol. Chem. 290 2015 168 182
84. R.D. Chetlin, L. Gutmann, M. Tarnopolsky, I.H. Ullrich, and R.A. Yeater Resistance training effectiveness in patients with Charcot-Marie-Tooth disease recommendations for exercise prescription Arch. Phys. Med. Rehabil. 85 2004 1217 1223
85. M.E. Shy Therapeutic strategies for the inherited neuropathies Neruomol. Med. 8 2006 255 278
86. D.N. Herrmann Experimental therapeutics in hereditary neuropathies: the past, the present, and the future Neurotherapeutics 5 2008 507 515
87. M. Wood, H. Yin, and G. McClorey Modulating the expression of disease genes with RNA-based therapy PLoS Genet. 3 2007 e109
88. R. Bhindi, R.G. Fahmy, H.C. Lowe, C.N. Chesterman, C.R. Dass, M.J. Cairns, E.G. Saravolac, L.Q. Sun, and L.M. Khachigian Brothers in arms: DNA enzymes, short interfering RNA, and the emerging wave of small-molecule nucleic acid-based gene-silencing strategies Am. J. Pathol. 171 2007 1079 1088
89. R. Kanasty, J.R. Dorkin, A. Vegas, and D. Anderson Delivery materials for siRNA therapeutics Nat. Mater. 12 2013 967 977
90. Y. Deng, C.C. Wang, K.W. Choy, Q. Du, J. Chen, Q. Wang, L. Li, T.K. Chung, and T. Tang Therapeutic potentials of gene silencing by RNA interference: principles, challenges, and new strategies Gene 538 2014 217 227
91. M. Nizzardo, C. Simone, M. Falcone, F. Locatelli, G. Riboldi, G.P. Comi, and S. Corti Human motor neuron generation from embryonic stem cells and induced pluripotent stem cells Cell. Mol. Life Sci. 67 2010 3837 3847
92. N.L. Payne, A. Sylvain, C. O'Brien, D. Herszfeld, G. Sun, and C.C. Bernard Application of human induced pluripotent stem cells for modeling and treating neurodegenerative diseases N. Biotechnol. 25 32 2015 212 228
93. M.A. Saporta, V. Dang, D. Volfson, B. Zou, X.S. Xie, A. Adebola, R.K. Liem, M. Shy, and J.T. Dimos Axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties Exp. Neurol. 263 2015 190 199
94. Y.W. Wang, W.T. Han, M. Jiang, C.X. Lu, X.F. Li, X. Zhang, and J.X. Li A novel mutation of the MFN2 gene in a Chinese family with Charcot-Marie-Tooth disease Genet. Mol. Res. 11 May 18 2012 1454 1459
95. S. Ajroud-Driss, F. Fecto, K. Ajroud, Y. Yang, S. Donkervoort, N. Siddique, and T. Siddique A novel de novo MFN2 mutation causing CMT2A with upper motor neuron signs Neurogenetics 10 2009 359 361
96. D.S. McCorquodale III, G. Montenegro, A. Peguero, N. Carlson, F. Speziani, J. Price, S.W. Taylor, M. Melanson, J.M. Vance, and S. Züchner Mutation screening of mitofusin 2 in Charcot-Marie-Tooth disease type 2 J. Neurol. 258 2011 1234 1239
97. K.W. Chung, B.C. Suh, S.Y. Cho, S.K. Choi, S.H. Kang, J.H. Yoo, J.Y. Hwang, and B.O. Choi Early-onset Charcot-Marie-Tooth patients with mitofusin 2 mutations and brain involvement J. Neurol. Neurosurg. Psychiatry 81 2010 1203 1206
98. R.X. Zhang, M. Fu, X.H. Zi, X.B. Li, F.F. Zhang, K. Xia, Q. Pan, Z.M. Hu, and B.S. Tang Mutation analysis of MFN2 gene in Chinese patients with Charcot-Marie-Tooth disease Zhonghua Yi Xue Za Zhi 89 2009 3324 3327
99. G.J. Braathen, J.C. Sand, A. Lobato, H. Høyer, and M.B. Russell MFN2 point mutations occur in 3.4% of Charcot-Marie-Tooth families. An investigation of 232 Norwegian CMT families BMC Med. Genet. 11 2010 48
100. C. Casasnovas, I. Banchs, J. Cassereau, N. Gueguen, A. Chevrollier, J.A. Martínez-Matos, D. Bonneau, and V. Volpini Phenotypic spectrum of MFN2 mutations in the Spanish population J. Med. Genet. 47 2010 249 256
101. I. Banchs, C. Casasnovas, J. Montero, J.A. Martínez-Matos, and V. Volpini Two Spanish families with Charcot-Marie-Tooth type 2A: clinical, electrophysiological and molecular findings Neuromuscul. Disord. 18 2008 974 978
102. H. Lv, L. Wang, W. Li, X. Qiao, Y. Li, Z. Wang, and Y. Yuan Mitofusin 2 gene mutation causing early-onset CMT2A with different progressive courses Clin. Neuropathol. 32 2013 16 23
103. R. Sivera, T. Sevilla, J.J. Vílchez, D. Martínez-Rubio, M.J. Chumillas, J.F. Vázquez, N. Muelas, L. Bataller, J.M. Millán, F. Palau, and C. Espinós Charcot-Marie-Tooth disease: genetic and clinical spectrum in a Spanish clinical series Neurology 81 2013 1617 1625
104. R. Del Bo, M. Moggio, M. Rango, S. Bonato, M.G. D'Angelo, S. Ghezzi, G. Airoldi, M.T. Bassi, M. Guglieri, L. Napoli, C. Lamperti, S. Corti, A. Federico, N. Bresolin, and G.P. Comi Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction Neurology 71 24 Dec 9 2008 1959 1966
105. A.B. Genari, V.H. Borghetti, S.P. Gouvêa, K.C. Bueno, P.L. dos Santos, A.C. dos Santos, A.A. Barreira, C.M. Lourenço, and W. Marques Jr. Characterizing the phenotypic manifestations of MFN2 R104W mutation in Charcot-Marie-Tooth type 2 Neuromuscul. Disord. 21 2011 428 432
106. J. Baets, T. Deconinck, E. De Vriendt, M. Zimoń, L. Yperzeele, K. Van Hoorenbeeck, K. Peeters, R. Spiegel, Y. Parman, B. Ceulemans, P. Van Bogaert, A. Pou-Serradell, G. Bernert, A. Dinopoulos, M. Auer-Grumbach, S.L. Sallinen, G.M. Fabrizi, F. Pauly, P. Van den Bergh, B. Bilir, E. Battaloglu, R.E. Madrid, D. Kabzińska, A. Kochanski, H. Topaloglu, G. Miller, A. Jordanova, V. Timmerman, and P. De Jonghe Genetic spectrum of hereditary neuropathies with onset in the first year of life Brain 134 2011 2664 2676
107. A. Abe, C. Numakura, K. Kijima, M. Hayashi, T. Hashimoto, and K. Hayasaka Molecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Japan J. Hum. Genet. 56 2011 364 368
108. K. Engelfried, M. Vorgerd, M. Hagedorn, G. Haas, J. Gilles, J.T. Epplen, and M. Meins Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2) BMC Med. Genet. 7 2006 53
109. C.J. Klein, G.W. Kimmel, S.J. Pittock, J.E. Engelstad, J.M. Cunningham, Y. Wu, and P.J. Dyck Large kindred evaluation of mitofusin 2 novel mutation, extremes of neurologic presentations, and preserved nerve mitochondria Arch. Neurol. 68 2011 1295 1302
110. K.P. Lin, B.W. Soong, C.C. Yang, L.W. Huang, M.H. Chang, I.H. Lee, A. Antonellis, and Y.C. Lee The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese in Taiwan PLoS One 6 2011 e29393
111. A. Vital, P. Latour, G. Sole, X. Ferrer, M. Rouanet, F. Tison, C. Vital, and C. Goizet A French family with Charcot-Marie-Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations Neuromuscul. Disord. 22 2012 735 741
112. C. Marchesi, C. Ciano, E. Salsano, L. Nanetti, M. Milani, C. Gellera, F. Taroni, G.M. Fabrizi, A. Uncini, and D. Pareyson Co-occurrence of amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease type 2A in a patient with a novel mutation in the mitofusin-2 gene Neuromuscul. Disord. 21 2011 129 131
113. C. Rouzier, S. Bannwarth, A. Chaussenot, A. Chevrollier, A. Verschueren, N. Bonello-Palot, K. Fragaki, A. Cano, J. Pouget, J.F. Pellissier, V. Procaccio, B. Chabrol, and V. Paquis-Flucklinger The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype Brain. 135 2012 23 34
114. R. Østern, T. Fagerheim, H. Hjellnes, B. Nygård, S.I. Mellgren, and Ø. Nilssen Diagnostic laboratory testing for Charcot Marie Tooth disease (CMT): the spectrum of gene defects in Norwegian patients with CMT and its implications for future genetic test strategies BMC Med. Genet. 14 2013 94
115. C.K. Ching, K.K. Lau, K.W. Yu, Y.W. Chan, and M.C. Mak A novel mitofusin 2 gene mutation causing Charcot-Marie-Tooth type 2A disease in a Chinese family Chin. Med. J. 123 2010 1466 1469
116. P. Vinci, and G. Lapi Anesthetic management in Charcot-Marie-Tooth disease type 2 due to a mutation in the mitofusin-2 gene J. Anaesthesiol. Clin. Pharmacol. 27 2011 286 287
117. R. Takahashi, T. Ikeda, A. Hamaguchi, K. Iwasa, and M. Yamada Coenzyme Q10 therapy in hereditary motor sensory neuropathy type VI with novel mitofusin 2 mutation Intern. Med. 51 2012 791 793
118. S.M. Feely, M. Laura, C.E. Siskind, S. Sottile, M. Davis, V.S. Gibbons, M.M. Reilly, and M.E. Shy MFN2 mutations cause severe phenotypes in most patients with CMT2A Neurology. 76 2011 1690 1696
119. J. Cassereau, C. Casasnovas, N. Gueguen, M.C. Malinge, V. Guillet, P. Reynier, D. Bonneau, P. Amati-Bonneau, I. Banchs, V. Volpini, V. Procaccio, and A. Chevrollier Simultaneous MFN2 and GDAP1 mutations cause major mitochondrial defects in a patient with CMT Neurology 76 2011 1524 1526