{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:14:23Z","timestamp":1791980063454,"version":"4.4.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T00:00:00Z","timestamp":1700870400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T00:00:00Z","timestamp":1700870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["GR- 2018-12365358"],"award-info":[{"award-number":["GR- 2018-12365358"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP19002"],"award-info":[{"award-number":["GGP19002"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NOMIS"},{"DOI":"10.13039\/100012352","name":"Universit\u00e0 degli Studi di Milano","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012352","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell. Mol. Life Sci."],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Mitofusin-2 (MFN2) is an outer mitochondrial membrane protein essential for mitochondrial networking in most cells. Autosomal dominant mutations in the\n                    <jats:italic>MFN2<\/jats:italic>\n                    gene cause Charcot\u2013Marie\u2013Tooth type 2A disease (CMT2A), a severe and disabling sensory-motor neuropathy that impacts the entire nervous system. Here, we propose a novel therapeutic strategy tailored to correcting the root genetic defect of CMT2A. Though mutant and wild-type\n                    <jats:italic>MFN2<\/jats:italic>\n                    mRNA are inhibited by RNA interference (RNAi), the wild-type protein is restored by overexpressing cDNA encoding functional\n                    <jats:italic>MFN2<\/jats:italic>\n                    modified to be resistant to RNAi. We tested this strategy in CMT2A patient-specific human induced pluripotent stem cell (iPSC)-differentiated motor neurons (MNs), demonstrating the correct silencing of endogenous\n                    <jats:italic>MFN2<\/jats:italic>\n                    and replacement with an exogenous copy of the functional wild-type gene. This approach significantly rescues the CMT2A MN phenotype in vitro, stabilizing the altered axonal mitochondrial distribution and correcting abnormal mitophagic processes. The\n                    <jats:italic>MFN2<\/jats:italic>\n                    molecular correction was also properly confirmed in vivo in the MitoCharc1 CMT2A transgenic mouse model after cerebrospinal fluid (CSF) delivery of the constructs into newborn mice using adeno-associated virus 9 (AAV9). Altogether, our data support the feasibility of a combined RNAi and gene therapy strategy for treating the broad spectrum of human diseases associated with\n                    <jats:italic>MFN2<\/jats:italic>\n                    mutations.\n                  <\/jats:p>","DOI":"10.1007\/s00018-023-05018-w","type":"journal-article","created":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T12:01:26Z","timestamp":1700913686000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot\u2013Marie\u2013Tooth type 2A"],"prefix":"10.1007","volume":"80","author":[{"given":"Federica","family":"Rizzo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc David","family":"Ruepp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Salani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Ottoboni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Abati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Melzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cordiglieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Pagliarani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"De Gioia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Anastasia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Taiana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Garbellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Lodato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Kunderfranco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Cazzato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Cartelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Lonati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nereo","family":"Bresolin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Comi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Nizzardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5734-7476","authenticated-orcid":false,"given":"Stefania","family":"Corti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,25]]},"reference":[{"key":"5018_CR1","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1083\/jcb.200211046","volume":"160","author":"H Chen","year":"2003","unstructured":"Chen H, Detmer SA, Ewald AJ et al (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189\u2013200. https:\/\/doi.org\/10.1083\/jcb.200211046","journal-title":"J Cell Biol"},{"key":"5018_CR2","doi-asserted-by":"publisher","first-page":"4232","DOI":"10.1523\/JNEUROSCI.6248-09.2010","volume":"30","author":"A Misko","year":"2010","unstructured":"Misko A, Jiang S, Wegorzewska I et al (2010) Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro\/Milton complex. J Neurosci 30:4232\u20134240. https:\/\/doi.org\/10.1523\/JNEUROSCI.6248-09.2010","journal-title":"J Neurosci"},{"key":"5018_CR3","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jns.2015.05.033","volume":"356","author":"G Stuppia","year":"2015","unstructured":"Stuppia G, Rizzo F, Riboldi G et al (2015) MFN2-related neuropathies: clinical features, molecular pathogenesis and therapeutic perspectives. J Neurol Sci 356:7\u201318. https:\/\/doi.org\/10.1016\/j.jns.2015.05.033","journal-title":"J Neurol Sci"},{"key":"5018_CR4","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1111\/brv.12378","volume":"93","author":"G Chandhok","year":"2018","unstructured":"Chandhok G, Lazarou M, Neumann B (2018) Structure, function, and regulation of mitofusin-2 in health and disease. Biol Rev Camb Philos Soc 93:933\u2013949. https:\/\/doi.org\/10.1111\/brv.12378","journal-title":"Biol Rev Camb Philos Soc"},{"key":"5018_CR5","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1126\/science.1231031","volume":"340","author":"Y Chen","year":"2013","unstructured":"Chen Y, Dorn GW (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471\u2013475. https:\/\/doi.org\/10.1126\/science.1231031","journal-title":"Science"},{"key":"5018_CR6","doi-asserted-by":"publisher","first-page":"2495","DOI":"10.1093\/hmg\/ddr139","volume":"20","author":"M Manczak","year":"2011","unstructured":"Manczak M, Calkins MJ, Reddy PH (2011) Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer\u2019s disease: implications for neuronal damage. Hum Mol Genet 20:2495\u20132509. https:\/\/doi.org\/10.1093\/hmg\/ddr139","journal-title":"Hum Mol Genet"},{"key":"5018_CR7","doi-asserted-by":"publisher","first-page":"101578","DOI":"10.1016\/j.arr.2022.101578","volume":"76","author":"A Manini","year":"2022","unstructured":"Manini A, Abati E, Comi GP et al (2022) Mitochondrial DNA homeostasis impairment and dopaminergic dysfunction: a trembling balance. Ageing Res Rev 76:101578. https:\/\/doi.org\/10.1016\/j.arr.2022.101578","journal-title":"Ageing Res Rev"},{"key":"5018_CR8","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1038\/ng1341","volume":"36","author":"S Z\u00fcchner","year":"2004","unstructured":"Z\u00fcchner S, Mersiyanova IV, Muglia M et al (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot\u2013Marie\u2013Tooth neuropathy type 2A. Nat Genet 36:449\u2013451. https:\/\/doi.org\/10.1038\/ng1341","journal-title":"Nat Genet"},{"key":"5018_CR9","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.expneurol.2009.05.003","volume":"218","author":"R Cartoni","year":"2009","unstructured":"Cartoni R, Martinou J-C (2009) Role of mitofusin 2 mutations in the physiopathology of Charcot\u2013Marie\u2013Tooth disease type 2A. Exp Neurol 218:268\u2013273. https:\/\/doi.org\/10.1016\/j.expneurol.2009.05.003","journal-title":"Exp Neurol"},{"key":"5018_CR10","doi-asserted-by":"publisher","first-page":"2093","DOI":"10.1093\/brain\/awl126","volume":"129","author":"K Verhoeven","year":"2006","unstructured":"Verhoeven K, Claeys KG, Z\u00fcchner S et al (2006) MFN2 mutation distribution and genotype\/phenotype correlation in Charcot\u2013Marie\u2013Tooth type 2. Brain 129:2093\u20132102. https:\/\/doi.org\/10.1093\/brain\/awl126","journal-title":"Brain"},{"key":"5018_CR11","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1083\/jcb.200611080","volume":"176","author":"SA Detmer","year":"2007","unstructured":"Detmer SA, Chan DC (2007) Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J Cell Biol 176:405\u2013414. https:\/\/doi.org\/10.1083\/jcb.200611080","journal-title":"J Cell Biol"},{"key":"5018_CR12","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.1212\/WNL.0b013e31821a441e","volume":"76","author":"SME Feely","year":"2011","unstructured":"Feely SME, Laura M, Siskind CE et al (2011) MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology 76:1690\u20131696. https:\/\/doi.org\/10.1212\/WNL.0b013e31821a441e","journal-title":"Neurology"},{"key":"5018_CR13","doi-asserted-by":"publisher","first-page":"3589","DOI":"10.1093\/brain\/awaa323","volume":"143","author":"M Pipis","year":"2020","unstructured":"Pipis M, Feely SME, Polke JM et al (2020) Natural history of Charcot\u2013Marie\u2013Tooth disease type 2A: a large international multicentre study. Brain 143:3589\u20133602. https:\/\/doi.org\/10.1093\/brain\/awaa323","journal-title":"Brain"},{"key":"5018_CR14","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1016\/S1474-4422(09)70110-3","volume":"8","author":"D Pareyson","year":"2009","unstructured":"Pareyson D, Marchesi C (2009) Diagnosis, natural history, and management of Charcot\u2013Marie\u2013Tooth disease. Lancet Neurol 8:654\u2013667. https:\/\/doi.org\/10.1016\/S1474-4422(09)70110-3","journal-title":"Lancet Neurol"},{"key":"5018_CR15","doi-asserted-by":"publisher","first-page":"6181","DOI":"10.1038\/s41598-022-10220-0","volume":"12","author":"E Abati","year":"2022","unstructured":"Abati E, Manini A, Velardo D et al (2022) Clinical and genetic features of a cohort of patients with MFN2-related neuropathy. Sci Rep 12:6181. https:\/\/doi.org\/10.1038\/s41598-022-10220-0","journal-title":"Sci Rep"},{"key":"5018_CR16","doi-asserted-by":"publisher","first-page":"1959","DOI":"10.1212\/01.wnl.0000327095.32005.a4","volume":"71","author":"R Del Bo","year":"2008","unstructured":"Del Bo R, Moggio M, Rango M et al (2008) Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction. Neurology 71:1959\u20131966. https:\/\/doi.org\/10.1212\/01.wnl.0000327095.32005.a4","journal-title":"Neurology"},{"key":"5018_CR17","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1136\/jnnp.2009.181669","volume":"81","author":"KW Chung","year":"2010","unstructured":"Chung KW, Suh BC, Cho SY et al (2010) Early-onset Charcot\u2013Marie\u2013Tooth patients with mitofusin 2 mutations and brain involvement. J Neurol Neurosurg Psychiatry 81:1203\u20131206. https:\/\/doi.org\/10.1136\/jnnp.2009.181669","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"5018_CR18","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/ana.24824","volume":"81","author":"M Lee","year":"2017","unstructured":"Lee M, Park C-H, Chung H-K et al (2017) Cerebral white matter abnormalities in patients with Charcot\u2013Marie\u2013tooth disease. Ann Neurol 81:147\u2013151. https:\/\/doi.org\/10.1002\/ana.24824","journal-title":"Ann Neurol"},{"key":"5018_CR19","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.1093\/brain\/awl174","volume":"129","author":"KW Chung","year":"2006","unstructured":"Chung KW, Kim SB, Park KD et al (2006) Early onset severe and late-onset mild Charcot\u2013Marie\u2013Tooth disease with mitofusin 2 (MFN2) mutations. Brain 129:2103\u20132118. https:\/\/doi.org\/10.1093\/brain\/awl174","journal-title":"Brain"},{"key":"5018_CR20","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1111\/jns.12155","volume":"21","author":"PJ Tomaselli","year":"2016","unstructured":"Tomaselli PJ, Rossor AM, Polke JM et al (2016) Semi-dominant mutations in MFN2-related neuropathy and implications for genetic counselling. J Peripher Nerv Syst 21:52\u201354. https:\/\/doi.org\/10.1111\/jns.12155","journal-title":"J Peripher Nerv Syst"},{"key":"5018_CR21","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1111\/jns.12145","volume":"20","author":"G Piscosquito","year":"2015","unstructured":"Piscosquito G, Saveri P, Magri S et al (2015) Mutational mechanisms in MFN2-related neuropathy: compound heterozygosity for recessive and semidominant mutations. J Peripher Nerv Syst 20:380\u2013386. https:\/\/doi.org\/10.1111\/jns.12145","journal-title":"J Peripher Nerv Syst"},{"key":"5018_CR22","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1212\/WNL.0b013e3182242d4d","volume":"77","author":"JM Polke","year":"2011","unstructured":"Polke JM, Laur\u00e1 M, Pareyson D et al (2011) Recessive axonal Charcot\u2013Marie\u2013Tooth disease due to compound heterozygous mitofusin 2 mutations. Neurology 77:168\u2013173. https:\/\/doi.org\/10.1212\/WNL.0b013e3182242d4d","journal-title":"Neurology"},{"key":"5018_CR23","doi-asserted-by":"publisher","first-page":"1678","DOI":"10.1212\/01.wnl.0000311275.89032.22","volume":"70","author":"GA Nicholson","year":"2008","unstructured":"Nicholson GA, Magdelaine C, Zhu D et al (2008) Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations. Neurology 70:1678\u20131681. https:\/\/doi.org\/10.1212\/01.wnl.0000311275.89032.22","journal-title":"Neurology"},{"key":"5018_CR24","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.expneurol.2008.01.010","volume":"211","author":"EA Amiott","year":"2008","unstructured":"Amiott EA, Lott P, Soto J et al (2008) Mitochondrial fusion and function in Charcot\u2013Marie\u2013Tooth type 2A patient fibroblasts with mitofusin 2 mutations. Exp Neurol 211:115\u2013127. https:\/\/doi.org\/10.1016\/j.expneurol.2008.01.010","journal-title":"Exp Neurol"},{"key":"5018_CR25","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1523\/JNEUROSCI.4798-06.2007","volume":"27","author":"RH Baloh","year":"2007","unstructured":"Baloh RH, Schmidt RE, Pestronk A, Milbrandt J (2007) Altered Axonal Mitochondrial transport in the pathogenesis of Charcot\u2013Marie\u2013Tooth disease from mitofusin 2 mutations. J Neurosci 27:422\u2013430. https:\/\/doi.org\/10.1523\/JNEUROSCI.4798-06.2007","journal-title":"J Neurosci"},{"key":"5018_CR26","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1002\/ana.21086","volume":"61","author":"D Loiseau","year":"2007","unstructured":"Loiseau D, Chevrollier A, Verny C et al (2007) Mitochondrial coupling defect in Charcot\u2013Marie\u2013Tooth type 2A disease. Ann Neurol 61:315\u2013323. https:\/\/doi.org\/10.1002\/ana.21086","journal-title":"Ann Neurol"},{"key":"5018_CR27","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1093\/brain\/awz064","volume":"142","author":"N Schiza","year":"2019","unstructured":"Schiza N, Georgiou E, Kagiava A et al (2019) Gene replacement therapy in a model of Charcot\u2013Marie\u2013Tooth 4C neuropathy. Brain 142:1227\u20131241. https:\/\/doi.org\/10.1093\/brain\/awz064","journal-title":"Brain"},{"key":"5018_CR28","doi-asserted-by":"publisher","first-page":"3528","DOI":"10.1093\/hmg\/ddz199","volume":"28","author":"A Kagiava","year":"2019","unstructured":"Kagiava A, Richter J, Tryfonos C et al (2019) Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X. Hum Mol Genet 28:3528\u20133542. https:\/\/doi.org\/10.1093\/hmg\/ddz199","journal-title":"Hum Mol Genet"},{"key":"5018_CR29","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","volume":"377","author":"JR Mendell","year":"2017","unstructured":"Mendell JR, Al-Zaidy S, Shell R et al (2017) Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377:1713\u20131722. https:\/\/doi.org\/10.1056\/NEJMoa1706198","journal-title":"N Engl J Med"},{"key":"5018_CR30","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1089\/hgtb.2012.120","volume":"23","author":"D Sondhi","year":"2012","unstructured":"Sondhi D, Johnson L, Purpura K et al (2012) Long-term expression and safety of administration of AAVrh. 10hCLN2 to the brain of rats and nonhuman primates for the treatment of late infantile neuronal ceroid lipofuscinosis. Hum Gene Ther Methods 23:324\u2013335. https:\/\/doi.org\/10.1089\/hgtb.2012.120","journal-title":"Hum Gene Ther Methods"},{"key":"5018_CR31","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.814174","volume":"12","author":"A Manini","year":"2021","unstructured":"Manini A, Abati E, Nuredini A et al (2021) Adeno-Associated Virus (AAV)-mediated gene therapy for Duchenne muscular dystrophy: the issue of transgene persistence. Front Neurol 12:814174. https:\/\/doi.org\/10.3389\/fneur.2021.814174","journal-title":"Front Neurol"},{"key":"5018_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2015.23","volume":"4","author":"JKW Lam","year":"2015","unstructured":"Lam JKW, Chow MYT, Zhang Y, Leung SWS (2015) siRNA Versus miRNA as therapeutics for gene silencing. Mol Ther Nucleic Acids 4:e252. https:\/\/doi.org\/10.1038\/mtna.2015.23","journal-title":"Mol Ther Nucleic Acids"},{"key":"5018_CR33","doi-asserted-by":"publisher","first-page":"4266","DOI":"10.1093\/hmg\/ddw258","volume":"25","author":"F Rizzo","year":"2016","unstructured":"Rizzo F, Ronchi D, Salani S et al (2016) Selective mitochondrial depletion, apoptosis resistance, and increased mitophagy in human Charcot\u2013Marie\u2013Tooth 2A motor neurons. Hum Mol Genet 25:4266\u20134281. https:\/\/doi.org\/10.1093\/hmg\/ddw258","journal-title":"Hum Mol Genet"},{"key":"5018_CR34","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1093\/brain\/awq082","volume":"133","author":"R Cartoni","year":"2010","unstructured":"Cartoni R, Arnaud E, M\u00e9dard J-J et al (2010) Expression of mitofusin 2R94Q in a transgenic mouse leads to Charcot\u2013Marie\u2013Tooth neuropathy type 2A. Brain 133:1460\u20131469. https:\/\/doi.org\/10.1093\/brain\/awq082","journal-title":"Brain"},{"key":"5018_CR35","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gni052","volume":"33","author":"A Paillusson","year":"2005","unstructured":"Paillusson A, Hirschi N, Vallan C et al (2005) A GFP-based reporter system to monitor nonsense-mediated mRNA decay. Nucleic Acids Res 33:e54. https:\/\/doi.org\/10.1093\/nar\/gni052","journal-title":"Nucleic Acids Res"},{"key":"5018_CR36","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1126\/science.1068999","volume":"296","author":"TR Brummelkamp","year":"2002","unstructured":"Brummelkamp TR, Bernards R, Agami R (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science 296:550\u2013553. https:\/\/doi.org\/10.1126\/science.1068999","journal-title":"Science"},{"key":"5018_CR37","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1038\/nsmb1081","volume":"13","author":"M B\u00fchler","year":"2006","unstructured":"B\u00fchler M, Steiner S, Mohn F et al (2006) EJC-independent degradation of nonsense immunoglobulin-mu mRNA depends on 3\u2032 UTR length. Nat Struct Mol Biol 13:462\u2013464. https:\/\/doi.org\/10.1038\/nsmb1081","journal-title":"Nat Struct Mol Biol"},{"key":"5018_CR38","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nbt.3049","volume":"33","author":"Y Maury","year":"2015","unstructured":"Maury Y, C\u00f4me J, Piskorowski RA et al (2015) Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes. Nat Biotechnol 33:89\u201396. https:\/\/doi.org\/10.1038\/nbt.3049","journal-title":"Nat Biotechnol"},{"key":"5018_CR39","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.acthis.2017.03.001","volume":"119","author":"AJ Valente","year":"2017","unstructured":"Valente AJ, Maddalena LA, Robb EL et al (2017) A simple ImageJ macro tool for analyzing mitochondrial network morphology in mammalian cell culture. Acta Histochem 119:315\u2013326. https:\/\/doi.org\/10.1016\/j.acthis.2017.03.001","journal-title":"Acta Histochem"},{"key":"5018_CR40","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1007\/s40265-019-01162-5","volume":"79","author":"SM Hoy","year":"2019","unstructured":"Hoy SM (2019) Onasemnogene abeparvovec: first global approval. Drugs 79:1255\u20131262. https:\/\/doi.org\/10.1007\/s40265-019-01162-5","journal-title":"Drugs"},{"key":"5018_CR41","doi-asserted-by":"publisher","first-page":"e1500078","DOI":"10.1126\/sciadv.1500078","volume":"1","author":"M Nizzardo","year":"2015","unstructured":"Nizzardo M, Simone C, Rizzo F et al (2015) Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model. Sci Adv 1:e1500078. https:\/\/doi.org\/10.1126\/sciadv.1500078","journal-title":"Sci Adv"},{"key":"5018_CR42","doi-asserted-by":"publisher","first-page":"165ra162","DOI":"10.1126\/scitranslmed.3004108","volume":"4","author":"S Corti","year":"2012","unstructured":"Corti S, Nizzardo M, Simone C et al (2012) Genetic correction of human induced pluripotent stem cells from patients with spinal muscular atrophy. Sci Transl Med 4:165ra162. https:\/\/doi.org\/10.1126\/scitranslmed.3004108","journal-title":"Sci Transl Med"},{"key":"5018_CR43","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.expneurol.2014.10.005","volume":"263","author":"MA Saporta","year":"2015","unstructured":"Saporta MA, Dang V, Volfson D et al (2015) Axonal Charcot\u2013Marie\u2013Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties. Exp Neurol 263:190\u2013199. https:\/\/doi.org\/10.1016\/j.expneurol.2014.10.005","journal-title":"Exp Neurol"},{"key":"5018_CR44","doi-asserted-by":"publisher","unstructured":"El Fissi N, Rojo M, Aouane A, et al (2020) Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy. EMBO Rep 21:50703. https:\/\/doi.org\/10.15252\/embr.202050703","DOI":"10.15252\/embr.202050703"},{"key":"5018_CR45","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1016\/j.bbagen.2016.03.007","volume":"1860","author":"G Bergamin","year":"2016","unstructured":"Bergamin G, Cieri D, Vazza G et al (2016) Zebrafish Tg(hb9:MTS-Kaede): a new in vivo tool for studying the axonal movement of mitochondria. Biochim Biophys Acta 1860:1247\u20131255. https:\/\/doi.org\/10.1016\/j.bbagen.2016.03.007","journal-title":"Biochim Biophys Acta"},{"key":"5018_CR46","doi-asserted-by":"publisher","first-page":"4145","DOI":"10.1523\/JNEUROSCI.6338-11.2012","volume":"32","author":"AL Misko","year":"2012","unstructured":"Misko AL, Sasaki Y, Tuck E et al (2012) Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration. J Neurosci 32:4145\u20134155. https:\/\/doi.org\/10.1523\/JNEUROSCI.6338-11.2012","journal-title":"J Neurosci"},{"key":"5018_CR47","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1126\/science.aao1785","volume":"360","author":"AG Rocha","year":"2018","unstructured":"Rocha AG, Franco A, Krezel AM et al (2018) MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot\u2013Marie\u2013Tooth disease type 2A. Science 360:336\u2013341. https:\/\/doi.org\/10.1126\/science.aao1785","journal-title":"Science"},{"key":"5018_CR48","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.3390\/ijms18091865","volume":"18","author":"SR Yoshii","year":"2017","unstructured":"Yoshii SR, Mizushima N (2017) Monitoring and measuring autophagy. Int J Mol Sci 18:1865. https:\/\/doi.org\/10.3390\/ijms18091865","journal-title":"Int J Mol Sci"},{"key":"5018_CR49","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1007\/s00018-015-2087-8","volume":"73","author":"A Hamacher-Brady","year":"2016","unstructured":"Hamacher-Brady A, Brady NR (2016) Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy. Cell Mol Life Sci 73:775\u2013795. https:\/\/doi.org\/10.1007\/s00018-015-2087-8","journal-title":"Cell Mol Life Sci"},{"key":"5018_CR50","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/nbt.1515","volume":"27","author":"KD Foust","year":"2009","unstructured":"Foust KD, Nurre E, Montgomery CL et al (2009) Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 27:59\u201365. https:\/\/doi.org\/10.1038\/nbt.1515","journal-title":"Nat Biotechnol"},{"key":"5018_CR51","doi-asserted-by":"publisher","first-page":"5121","DOI":"10.1007\/s12035-020-02081-3","volume":"57","author":"R De Gioia","year":"2020","unstructured":"De Gioia R, Citterio G, Abati E et al (2020) Animal models of CMT2A: state-of-art and therapeutic implications. Mol Neurobiol 57:5121\u20135129. https:\/\/doi.org\/10.1007\/s12035-020-02081-3","journal-title":"Mol Neurobiol"},{"key":"5018_CR52","doi-asserted-by":"publisher","first-page":"522","DOI":"10.3390\/ph6040522","volume":"6","author":"H Hohjoh","year":"2013","unstructured":"Hohjoh H (2013) Disease-causing allele-specific silencing by RNA interference. Pharmaceuticals (Basel) 6:522\u2013535. https:\/\/doi.org\/10.3390\/ph6040522","journal-title":"Pharmaceuticals (Basel)"},{"key":"5018_CR53","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.gene.2005.11.006","volume":"371","author":"X Feng","year":"2006","unstructured":"Feng X, Zhao P, He Y, Zuo Z (2006) Allele-specific silencing of Alzheimer\u2019s disease genes: the amyloid precursor protein genes with Swedish or London mutations. Gene 371:68\u201374. https:\/\/doi.org\/10.1016\/j.gene.2005.11.006","journal-title":"Gene"},{"key":"5018_CR54","doi-asserted-by":"publisher","first-page":"e241","DOI":"10.1038\/mtna.2015.14","volume":"4","author":"M Takahashi","year":"2015","unstructured":"Takahashi M, Suzuki M, Fukuoka M et al (2015) Normalization of overexpressed \u03b1-synuclein causing Parkinson\u2019s disease by a moderate gene silencing with RNA interference. Mol Ther Nucleic Acids 4:e241. https:\/\/doi.org\/10.1038\/mtna.2015.14","journal-title":"Mol Ther Nucleic Acids"},{"key":"5018_CR55","doi-asserted-by":"publisher","first-page":"2178","DOI":"10.1038\/mt.2011.201","volume":"19","author":"JB Carroll","year":"2011","unstructured":"Carroll JB, Warby SC, Southwell AL et al (2011) Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene \/ allele-specific silencing of mutant huntingtin. Mol Ther 19:2178\u20132185. https:\/\/doi.org\/10.1038\/mt.2011.201","journal-title":"Mol Ther"},{"key":"5018_CR56","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1038\/nn.4014","volume":"18","author":"K Be\u010danovi\u0107","year":"2015","unstructured":"Be\u010danovi\u0107 K, N\u00f8rrem\u00f8lle A, Neal SJ et al (2015) A SNP in the HTT promoter alters NF-\u03baB binding and is a bidirectional genetic modifier of Huntington disease. Nat Neurosci 18:807\u2013816. https:\/\/doi.org\/10.1038\/nn.4014","journal-title":"Nat Neurosci"},{"key":"5018_CR57","doi-asserted-by":"publisher","first-page":"2380","DOI":"10.1093\/hmg\/ddq111","volume":"19","author":"S Alves","year":"2010","unstructured":"Alves S, Nascimento-Ferreira I, Dufour N et al (2010) Silencing ataxin-3 mitigates degeneration in a rat model of Machado\u2013Joseph disease: no role for wild-type ataxin-3? Hum Mol Genet 19:2380\u20132394. https:\/\/doi.org\/10.1093\/hmg\/ddq111","journal-title":"Hum Mol Genet"},{"key":"5018_CR58","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1111\/j.1471-4159.2004.02860.x","volume":"92","author":"XG Xia","year":"2005","unstructured":"Xia XG, Zhou H, Zhou S et al (2005) An RNAi strategy for treatment of amyotrophic lateral sclerosis caused by mutant Cu, Zn superoxide dismutase. J Neurochem 92:362\u2013367. https:\/\/doi.org\/10.1111\/j.1471-4159.2004.02860.x","journal-title":"J Neurochem"},{"key":"5018_CR59","doi-asserted-by":"publisher","first-page":"132933","DOI":"10.1016\/j.neulet.2017.06.052","volume":"710","author":"EF Smith","year":"2019","unstructured":"Smith EF, Shaw PJ, De Vos KJ (2019) The role of mitochondria in amyotrophic lateral sclerosis. Neurosci Lett 710:132933. https:\/\/doi.org\/10.1016\/j.neulet.2017.06.052","journal-title":"Neurosci Lett"},{"key":"5018_CR60","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1016\/j.bbabio.2015.05.022","volume":"1847","author":"BAI Payne","year":"2015","unstructured":"Payne BAI, Chinnery PF (2015) Mitochondrial dysfunction in aging: much progress but many unresolved questions. Biochim Biophys Acta 1847:1347\u20131353. https:\/\/doi.org\/10.1016\/j.bbabio.2015.05.022","journal-title":"Biochim Biophys Acta"},{"key":"5018_CR61","doi-asserted-by":"publisher","first-page":"e147307","DOI":"10.1172\/JCI147307","volume":"131","author":"Y Zhou","year":"2021","unstructured":"Zhou Y, Carmona S, Muhammad AKMG et al (2021) Restoring mitofusin balance prevents axonal degeneration in a Charcot\u2013Marie\u2013Tooth type 2A model. J Clin Invest 131:e147307-147307. https:\/\/doi.org\/10.1172\/JCI147307","journal-title":"J Clin Invest"},{"key":"5018_CR62","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/mt.2014.210","volume":"23","author":"K Meyer","year":"2015","unstructured":"Meyer K, Ferraiuolo L, Schmelzer L et al (2015) Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose\u2013response study in mice and nonhuman primates. Mol Ther 23:477\u2013487. https:\/\/doi.org\/10.1038\/mt.2014.210","journal-title":"Mol Ther"},{"key":"5018_CR63","doi-asserted-by":"publisher","first-page":"100346","DOI":"10.1016\/j.xcrm.2021.100346","volume":"2","author":"H Chaytow","year":"2021","unstructured":"Chaytow H, Faller KME, Huang Y-T, Gillingwater TH (2021) Spinal muscular atrophy: from approved therapies to future therapeutic targets for personalized medicine. Cell Rep Med 2:100346. https:\/\/doi.org\/10.1016\/j.xcrm.2021.100346","journal-title":"Cell Rep Med"},{"key":"5018_CR64","doi-asserted-by":"crossref","unstructured":"Miyake K, Miyake N, Shimada T, et al (2017) Neonatal gene therapy for inherited disorders. IntechOpen","DOI":"10.5772\/intechopen.69218"},{"key":"5018_CR65","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1529-8027.2011.00324.x","volume":"16","author":"MM Reilly","year":"2011","unstructured":"Reilly MM, Murphy SM, Laur\u00e1 M (2011) Charcot\u2013Marie-\u2013Tooth disease. J Peripher Nerv Syst 16:1\u201314. https:\/\/doi.org\/10.1111\/j.1529-8027.2011.00324.x","journal-title":"J Peripher Nerv Syst"},{"key":"5018_CR66","doi-asserted-by":"publisher","first-page":"113281","DOI":"10.1016\/j.expneurol.2020.113281","volume":"328","author":"C Picci","year":"2020","unstructured":"Picci C, Wong VSC, Costa CJ et al (2020) HDAC6 inhibition promotes \u03b1-tubulin acetylation and ameliorates CMT2A peripheral neuropathy in mice. Exp Neurol 328:113281. https:\/\/doi.org\/10.1016\/j.expneurol.2020.113281","journal-title":"Exp Neurol"},{"key":"5018_CR67","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1261\/rna.28106","volume":"12","author":"Y Fedorov","year":"2006","unstructured":"Fedorov Y, Anderson EM, Birmingham A et al (2006) Off-target effects by siRNA can induce toxic phenotype. RNA 12:1188\u20131196. https:\/\/doi.org\/10.1261\/rna.28106","journal-title":"RNA"},{"key":"5018_CR68","doi-asserted-by":"publisher","first-page":"e152817","DOI":"10.1172\/JCI152817","volume":"131","author":"TO Crawford","year":"2021","unstructured":"Crawford TO, Sumner CJ (2021) Assuring long-term safety of highly effective gene-modulating therapeutics for rare diseases. J Clin Invest 131:e152817. https:\/\/doi.org\/10.1172\/JCI152817","journal-title":"J Clin Invest"},{"key":"5018_CR69","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.omtm.2020.08.018","volume":"19","author":"B Belbellaa","year":"2020","unstructured":"Belbellaa B, Reutenauer L, Messaddeq N et al (2020) High levels of frataxin overexpression lead to mitochondrial and cardiac toxicity in mouse models. Mol Ther Methods Clin Dev 19:120\u2013138. https:\/\/doi.org\/10.1016\/j.omtm.2020.08.018","journal-title":"Mol Ther Methods Clin Dev"},{"key":"5018_CR70","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1038\/s41593-021-00827-3","volume":"24","author":"M Van Alstyne","year":"2021","unstructured":"Van Alstyne M, Tattoli I, Delestree N et al (2021) Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensory-motor circuit. Nat Neurosci 24:930\u2013940. https:\/\/doi.org\/10.1038\/s41593-021-00827-3","journal-title":"Nat Neurosci"},{"key":"5018_CR71","doi-asserted-by":"publisher","first-page":"2693","DOI":"10.1093\/hmg\/ddm223","volume":"16","author":"A Fraldi","year":"2007","unstructured":"Fraldi A, Hemsley K, Crawley A et al (2007) Functional correction of CNS lesions in an MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes. Hum Mol Genet 16:2693\u20132702. https:\/\/doi.org\/10.1093\/hmg\/ddm223","journal-title":"Hum Mol Genet"}],"container-title":["Cellular and Molecular Life Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-023-05018-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00018-023-05018-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-023-05018-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T22:12:31Z","timestamp":1703023951000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00018-023-05018-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,25]]},"references-count":71,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["5018"],"URL":"https:\/\/doi.org\/10.1007\/s00018-023-05018-w","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-2817290\/v1","asserted-by":"object"}]},"ISSN":["1420-682X","1420-9071"],"issn-type":[{"value":"1420-682X","type":"print"},{"value":"1420-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,25]]},"assertion":[{"value":"14 April 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2023","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 October 2023","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 November 2023","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All animal experiments strictly follow the guidelines of the Italian Ministry of Health in compliance with U.S. National Institutes of Health Guide for the Care and Use of Laboratory Animals.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All the authors have approved and agreed to publish this manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"373"}}