{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:50:29Z","timestamp":1787637029835,"version":"build-2736575974"},"reference-count":51,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Korean Health Technology R&D Project, Ministry of Health & Welfare","award":["HR22C1363"],"award-info":[{"award-number":["HR22C1363"]}]},{"name":"Korean Health Technology R&D Project, Ministry of Health & Welfare","award":["RS-2024-00438444"],"award-info":[{"award-number":["RS-2024-00438444"]}]},{"name":"the Regenerative Medicine co-funded by Ministry of Science and ICT and Ministry of Health and Welfare","award":["23C0115L1"],"award-info":[{"award-number":["23C0115L1"]}]},{"name":"Future Medicine 2030 Project of the Samsung Medical Center","award":["SMO1240041"],"award-info":[{"award-number":["SMO1240041"]}]},{"DOI":"10.13039\/501100003725","name":"Korean National Research Foundation","doi-asserted-by":"crossref","award":["RS-2025-00515382"],"award-info":[{"award-number":["RS-2025-00515382"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002551","name":"Seoul National University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002551","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Charcot\u2013Marie\u2013Tooth disease type 2Z (CMT2Z) is an inherited axonal neuropathy caused by haploinsufficiency of microrchidia CW-type zinc finger protein 2 (<jats:italic>MORC2<\/jats:italic>), which leads to elevated hydroxyl radical levels, reduced ATPase activity, and apoptosis-mediated neuromuscular degeneration. CMT2Z presents with severe clinical manifestations, yet no widely applicable and affordable treatment has been developed. While gene therapy presents a theoretical solution, its feasibility remains constrained by prohibitive costs and delivery challenges. We observed sex-specific differences in muscle function in a CMT2Z mouse model carrying the microrchidia CW-type zinc finger protein 2A (<jats:italic>Morc2a<\/jats:italic>) p.S87L variant, with males exhibiting more severe weakness, suggesting a protective role of estradiol in females. Thus, we hypothesized that identifying and utilizing this factor could contribute to CMT2Z drug development. We found that estradiol stabilizes the <jats:italic>Morc2a<\/jats:italic> variant protein by inhibiting autophagy, independently of specific estrogen receptors, thereby mitigating hydroxyl radical\u2013induced mitochondrial aggregation and apoptosis while restoring ATPase function. Subcutaneous implantation of estradiol pellets in the CMT2Z mouse model significantly improved <jats:italic>Morc2a<\/jats:italic> protein stability in the <jats:italic>quadriceps femoris<\/jats:italic> and sciatic nerve, reversed mitochondrial aggregation, and ameliorated both muscular and peripheral nerve degeneration. Notably, symptomatic <jats:italic>Morc2a<\/jats:italic> p.S87L mice exhibited robust peripheral nerve regeneration, demonstrating estradiol\u2019s ability to restore function rather than merely delay disease progression. Moreover, the therapeutic effects were reproduced in human <jats:italic>MORC2<\/jats:italic> p.R252W variants, further confirming its translational potential. As an FDA-approved compound with well-characterized pharmacokinetics, estradiol represents a rapidly deployable strategy for treating CMT2Z. This study highlights the pivotal role of oxidative stress in the pathophysiology of CMT2Z and identifies MORC2 stabilization as a promising intervention. Moreover, the findings advocate for repurposing existing therapeutics to address rare genetic disorders, broadening treatment paradigms for neuromuscular diseases beyond CMT2Z.<\/jats:p>","DOI":"10.1007\/s00401-025-02922-2","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T21:38:49Z","timestamp":1754343529000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Estradiol rescues male hydroxyl radical-mediated Charcot-Marie-Tooth 2Z by Morc2a stabilization through autophagy inhibition in a murine model"],"prefix":"10.1007","volume":"150","author":[{"given":"Ji Won","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Hyun","family":"Nam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geon Seong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Yoon","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Young","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Pil","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hyung","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung-Ok","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Cheong","family":"Yeom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"2922_CR1","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1523\/JNEUROSCI.0906-12.2013","volume":"33","author":"MW Amoroso","year":"2013","unstructured":"Amoroso MW, Croft GF, Williams DJ, O\u2019Keeffe S, Carrasco MA, Davis AR et al (2013) Accelerated high-yield generation of limb-innervating motor neurons from human stem cells. J Neurosci 33:574\u2013586. https:\/\/doi.org\/10.1523\/JNEUROSCI.0906-12.2013","journal-title":"J Neurosci"},{"key":"2922_CR2","first-page":"327","volume":"23","author":"E Babusikova","year":"2004","unstructured":"Babusikova E, Kaplan P, Lehotsky J, Jesenak M, Dobrota D (2004) Oxidative modification of rat cardiac mitochondrial membranes and myofibrils by hydroxyl radicals. Gen Physiol Biophys 23:327\u2013335","journal-title":"Gen Physiol Biophys"},{"key":"2922_CR3","doi-asserted-by":"publisher","DOI":"10.1155\/2009\/985415","volume":"2009","author":"I Banchs","year":"2009","unstructured":"Banchs I, Casasnovas C, Alberti A, De Jorge L, Povedano M, Montero J et al (2009) Diagnosis of Charcot-Marie-Tooth disease. J Biomed Biotechnol 2009:985415. https:\/\/doi.org\/10.1155\/2009\/985415","journal-title":"J Biomed Biotechnol"},{"key":"2922_CR4","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1093\/emboj\/17.1.37","volume":"17","author":"E Bossy-Wetzel","year":"1998","unstructured":"Bossy-Wetzel E, Newmeyer DD, Green DR (1998) Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 17:37\u201349. https:\/\/doi.org\/10.1093\/emboj\/17.1.37","journal-title":"EMBO J"},{"key":"2922_CR5","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s40478-015-0271-6","volume":"4","author":"D Cacabelos","year":"2016","unstructured":"Cacabelos D, Ramirez-Nunez O, Granado-Serrano AB, Torres P, Ayala V, Moiseeva V et al (2016) Early and gender-specific differences in spinal cord mitochondrial function and oxidative stress markers in a mouse model of ALS. Acta Neuropathol Commun 4:3. https:\/\/doi.org\/10.1186\/s40478-015-0271-6","journal-title":"Acta Neuropathol Commun"},{"key":"2922_CR6","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/ejhg.2008.185","volume":"17","author":"E Canu","year":"2009","unstructured":"Canu E, Boccardi M, Ghidoni R, Benussi L, Testa C, Pievani M et al (2009) H1 haplotype of the MAPT gene is associated with lower regional gray matter volume in healthy carriers. Eur J Hum Genet 17:287\u2013294. https:\/\/doi.org\/10.1038\/ejhg.2008.185","journal-title":"Eur J Hum Genet"},{"key":"2922_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-024-05964-6","volume":"7","author":"C Chen","year":"2024","unstructured":"Chen C, Li H, Zhang J, Cheng SC (2024) Exploring the limitations of mitochondrial dye as a genuine horizontal mitochondrial transfer surrogate. Commun Biol 7:281. https:\/\/doi.org\/10.1038\/s42003-024-05964-6","journal-title":"Commun Biol"},{"key":"2922_CR8","doi-asserted-by":"publisher","first-page":"839005","DOI":"10.3389\/fendo.2022.839005","volume":"13","author":"P Chen","year":"2022","unstructured":"Chen P, Li B, Ou-Yang L (2022) Role of estrogen receptors in health and disease. Front Endocrinol (Lausanne) 13:839005. https:\/\/doi.org\/10.3389\/fendo.2022.839005","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2922_CR9","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/brain\/awae017","volume":"147","author":"HY Chung","year":"2024","unstructured":"Chung HY, Lee GS, Nam SH, Lee JH, Han JP, Song S et al (2024) Morc2a variants cause hydroxyl radical-mediated neuropathy and are rescued by restoring GHKL ATPase. Brain 147:2114\u20132127. https:\/\/doi.org\/10.1093\/brain\/awae017","journal-title":"Brain"},{"key":"2922_CR10","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1021\/acssynbio.2c00589","volume":"12","author":"LT Collins","year":"2023","unstructured":"Collins LT, Ponnazhagan S, Curiel DT (2023) Synthetic biology design as a paradigm shift toward manufacturing affordable adeno-associated virus gene therapies. ACS Synth Biol 12:17\u201326. https:\/\/doi.org\/10.1021\/acssynbio.2c00589","journal-title":"ACS Synth Biol"},{"key":"2922_CR11","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1017\/S0266462307051550","volume":"23","author":"MF Drummond","year":"2007","unstructured":"Drummond MF, Wilson DA, Kanavos P, Ubel P, Rovira J (2007) Assessing the economic challenges posed by orphan drugs. Int J Technol Assess Health Care 23:36\u201342. https:\/\/doi.org\/10.1017\/S0266462307051550","journal-title":"Int J Technol Assess Health Care"},{"key":"2922_CR12","doi-asserted-by":"publisher","first-page":"e2303926","DOI":"10.1002\/advs.202303926","volume":"10","author":"H Gao","year":"2023","unstructured":"Gao H, Sun L, Li J, Zhou Q, Xu H, Ma XN et al (2023) Illumination of hydroxyl radical in kidney injury and high-throughput screening of natural protectants using a fluorescent\/photoacoustic probe. Adv Sci (Weinh) 10:e2303926. https:\/\/doi.org\/10.1002\/advs.202303926","journal-title":"Adv Sci (Weinh)"},{"key":"2922_CR13","doi-asserted-by":"publisher","first-page":"5579","DOI":"10.1038\/sj.onc.1206576","volume":"22","author":"N Haga","year":"2003","unstructured":"Haga N, Fujita N, Tsuruo T (2003) Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis. Oncogene 22:5579\u20135585. https:\/\/doi.org\/10.1038\/sj.onc.1206576","journal-title":"Oncogene"},{"key":"2922_CR14","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1007\/400_2009_19","volume":"48","author":"EA Huebner","year":"2009","unstructured":"Huebner EA, Strittmatter SM (2009) Axon regeneration in the peripheral and central nervous systems. Results Probl Cell Differ 48:339\u2013351. https:\/\/doi.org\/10.1007\/400_2009_19","journal-title":"Results Probl Cell Differ"},{"key":"2922_CR15","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.896854","volume":"16","author":"A Jacquier","year":"2022","unstructured":"Jacquier A, Roubille S, Lomonte P, Schaeffer L (2022) Microrchidia CW-type zinc finger 2, a chromatin modifier in a spectrum of peripheral neuropathies. Front Cell Neurosci 16:896854. https:\/\/doi.org\/10.3389\/fncel.2022.896854","journal-title":"Front Cell Neurosci"},{"key":"2922_CR16","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1097\/SHK.0b013e318292300d","volume":"39","author":"A Kholmukhamedov","year":"2013","unstructured":"Kholmukhamedov A, Schwartz JM, Lemasters JJ (2013) Isolated mitochondria infusion mitigates ischemia-reperfusion injury of the liver in rats: mitotracker probes and mitochondrial membrane potential. Shock 39:543. https:\/\/doi.org\/10.1097\/SHK.0b013e318292300d","journal-title":"Shock"},{"key":"2922_CR17","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.sxmr.2019.03.006","volume":"7","author":"GE Kohn","year":"2019","unstructured":"Kohn GE, Rodriguez KM, Hotaling J, Pastuszak AW (2019) The history of estrogen therapy. Sex Med Rev 7:416\u2013421. https:\/\/doi.org\/10.1016\/j.sxmr.2019.03.006","journal-title":"Sex Med Rev"},{"key":"2922_CR18","doi-asserted-by":"publisher","DOI":"10.3390\/biom10040500","volume":"10","author":"IV Kondakova","year":"2020","unstructured":"Kondakova IV, Shashova EE, Sidenko EA, Astakhova TM, Zakharova LA, Sharova NP (2020) Estrogen receptors and ubiquitin proteasome system: mutual regulation. Biomolecules 10:Doi 10.3390\/biom10040500","journal-title":"Biomolecules"},{"key":"2922_CR19","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.049123","author":"GS Lee","year":"2021","unstructured":"Lee GS, Kwak G, Bae JH, Han JP, Nam SH, Lee JH et al (2021) Morc2a p. S87L mutant mice develop peripheral and central neuropathies associated with neuronal DNA damage and apoptosis. Dis Model Mech. https:\/\/doi.org\/10.1242\/dmm.049123","journal-title":"Dis Model Mech"},{"key":"2922_CR20","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s12929-015-0154-y","volume":"22","author":"J Lee","year":"2015","unstructured":"Lee J, Jung SC, Joo J, Choi YR, Moon HW, Kwak G et al (2015) Overexpression of mutant HSP27 causes axonal neuropathy in mice. J Biomed Sci 22:43. https:\/\/doi.org\/10.1186\/s12929-015-0154-y","journal-title":"J Biomed Sci"},{"key":"2922_CR21","doi-asserted-by":"publisher","first-page":"97941","DOI":"10.18632\/oncotarget.18556","volume":"8","author":"XH Liao","year":"2017","unstructured":"Liao XH, Zhang Y, Dong WJ, Shao ZM, Li DQ (2017) Chromatin remodeling protein MORC2 promotes breast cancer invasion and metastasis through a PRD domain-mediated interaction with CTNND1. Oncotarget 8:97941\u201397954. https:\/\/doi.org\/10.18632\/oncotarget.18556","journal-title":"Oncotarget"},{"key":"2922_CR22","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1016\/j.bbadis.2011.05.001","volume":"1812","author":"A Maggi","year":"2011","unstructured":"Maggi A (2011) Liganded and unliganded activation of estrogen receptor and hormone replacement therapies. Biochim Biophys Acta 1812:1054\u20131060. https:\/\/doi.org\/10.1016\/j.bbadis.2011.05.001","journal-title":"Biochim Biophys Acta"},{"key":"2922_CR23","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1097\/WCO.0000000000000774","volume":"33","author":"M Manto","year":"2020","unstructured":"Manto M, Gandini J, Feil K, Strupp M (2020) Cerebellar ataxias: an update. Curr Opin Neurol 33:150\u2013160. https:\/\/doi.org\/10.1097\/WCO.0000000000000774","journal-title":"Curr Opin Neurol"},{"key":"2922_CR24","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1586\/14737175.2015.1017471","volume":"15","author":"S Mathis","year":"2015","unstructured":"Mathis S, Magy L, Vallat JM (2015) Therapeutic options in Charcot-Marie-Tooth diseases. Expert Rev Neurother 15:355\u2013366. https:\/\/doi.org\/10.1586\/14737175.2015.1017471","journal-title":"Expert Rev Neurother"},{"key":"2922_CR25","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.pmr.2012.06.011","volume":"23","author":"CM McDonald","year":"2012","unstructured":"McDonald CM (2012) Clinical approach to the diagnostic evaluation of hereditary and acquired neuromuscular diseases. Phys Med Rehabil Clin N Am 23:495\u2013563. https:\/\/doi.org\/10.1016\/j.pmr.2012.06.011","journal-title":"Phys Med Rehabil Clin N Am"},{"key":"2922_CR26","doi-asserted-by":"publisher","first-page":"e14989","DOI":"10.14814\/phy2.14989","volume":"9","author":"CL Meyer-Olesen","year":"2021","unstructured":"Meyer-Olesen CL, Lindhard K, Jorgensen NR, Goetze JP, Bomholt T, Jensen BL et al (2021) Flow reduction of a high-flow arteriovenous fistula in a hemodialysis patient reveals changes in natriuretic and renin-angiotensin system hormones of relevance for kidney function. Physiol Rep 9:e14989. https:\/\/doi.org\/10.14814\/phy2.14989","journal-title":"Physiol Rep"},{"key":"2922_CR27","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-10-244","volume":"10","author":"B Montgomery","year":"2010","unstructured":"Montgomery B, Nelson PS, Vessella R, Kalhorn T, Hess D, Corey E (2010) Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer. BMC Cancer 10:244. https:\/\/doi.org\/10.1186\/1471-2407-10-244","journal-title":"BMC Cancer"},{"key":"2922_CR28","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.mce.2008.04.008","volume":"290","author":"M Morissette","year":"2008","unstructured":"Morissette M, Al Sweidi S, Callier S, Di Paolo T (2008) Estrogen and SERM neuroprotection in animal models of Parkinson\u2019s disease. Mol Cell Endocrinol 290:60\u201369. https:\/\/doi.org\/10.1016\/j.mce.2008.04.008","journal-title":"Mol Cell Endocrinol"},{"key":"2922_CR29","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.yfrne.2007.12.005","volume":"29","author":"J Nilsen","year":"2008","unstructured":"Nilsen J (2008) Estradiol and neurodegenerative oxidative stress. Front Neuroendocrinol 29:463\u2013475. https:\/\/doi.org\/10.1016\/j.yfrne.2007.12.005","journal-title":"Front Neuroendocrinol"},{"key":"2922_CR30","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1016\/s0029-7844(99)00643-2","volume":"95","author":"M Notelovitz","year":"2000","unstructured":"Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J (2000) Initial 17beta-estradiol dose for treating vasomotor symptoms. Obstet Gynecol 95:726\u2013731. https:\/\/doi.org\/10.1016\/s0029-7844(99)00643-2","journal-title":"Obstet Gynecol"},{"key":"2922_CR31","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1111\/jns.12530","volume":"28","author":"JH Park","year":"2023","unstructured":"Park JH, Kwon HM, Nam DE, Kim HJ, Nam SH, Kim SB et al (2023) INF2 mutations in patients with a broad phenotypic spectrum of Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis. J Peripher Nerv Syst 28:108\u2013118. https:\/\/doi.org\/10.1111\/jns.12530","journal-title":"J Peripher Nerv Syst"},{"key":"2922_CR32","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.jsbmb.2013.12.011","volume":"142","author":"JV Pinkerton","year":"2014","unstructured":"Pinkerton JV, Thomas S (2014) Use of SERMs for treatment in postmenopausal women. J Steroid Biochem Mol Biol 142:142\u2013154. https:\/\/doi.org\/10.1016\/j.jsbmb.2013.12.011","journal-title":"J Steroid Biochem Mol Biol"},{"key":"2922_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4449","volume":"5","author":"Q Qu","year":"2014","unstructured":"Qu Q, Li D, Louis KR, Li X, Yang H, Sun Q et al (2014) High-efficiency motor neuron differentiation from human pluripotent stem cells and the function of Islet-1. Nat Commun 5:3449. https:\/\/doi.org\/10.1038\/ncomms4449","journal-title":"Nat Commun"},{"key":"2922_CR34","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/s41434-018-0005-z","volume":"25","author":"MY Rincon","year":"2018","unstructured":"Rincon MY, de Vin F, Duque SI, Fripont S, Castaldo SA, Bouhuijzen-Wenger J et al (2018) Widespread transduction of astrocytes and neurons in the mouse central nervous system after systemic delivery of a self-complementary AAV-PHP.B vector. Gene Ther 25:83\u201392. https:\/\/doi.org\/10.1038\/s41434-018-0005-z","journal-title":"Gene Ther"},{"key":"2922_CR35","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1001\/jama.2024.5613","volume":"331","author":"DM Rind","year":"2024","unstructured":"Rind DM (2024) The FDA and gene therapy for Duchenne muscular dystrophy. JAMA 331:1705\u20131706. https:\/\/doi.org\/10.1001\/jama.2024.5613","journal-title":"JAMA"},{"key":"2922_CR36","doi-asserted-by":"publisher","first-page":"R297","DOI":"10.1530\/ERC-17-0153","volume":"24","author":"N Russell","year":"2017","unstructured":"Russell N, Cheung A, Grossmann M (2017) Estradiol for the mitigation of adverse effects of androgen deprivation therapy. Endocr Relat Cancer 24:R297\u2013R313. https:\/\/doi.org\/10.1530\/ERC-17-0153","journal-title":"Endocr Relat Cancer"},{"key":"2922_CR37","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1093\/brain\/awv311","volume":"139","author":"T Sevilla","year":"2016","unstructured":"Sevilla T, Lupo V, Martinez-Rubio D, Sancho P, Sivera R, Chumillas MJ et al (2016) Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease. Brain 139:62\u201372. https:\/\/doi.org\/10.1093\/brain\/awv311","journal-title":"Brain"},{"key":"2922_CR38","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1038\/nprot.2012.116","volume":"7","author":"Y Shi","year":"2012","unstructured":"Shi Y, Kirwan P, Livesey FJ (2012) Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc 7:1836\u20131846. https:\/\/doi.org\/10.1038\/nprot.2012.116","journal-title":"Nat Protoc"},{"key":"2922_CR39","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2023.105074","volume":"146","author":"A Shvetcov","year":"2023","unstructured":"Shvetcov A, Ruitenberg MJ, Delerue F, Gold WA, Brown DA, Finney CA (2023) The neuroprotective effects of estrogen and estrogenic compounds in spinal cord injury. Neurosci Biobehav Rev 146:105074. https:\/\/doi.org\/10.1016\/j.neubiorev.2023.105074","journal-title":"Neurosci Biobehav Rev"},{"key":"2922_CR40","doi-asserted-by":"publisher","first-page":"157","DOI":"10.3389\/fnins.2020.00157","volume":"14","author":"YJ Song","year":"2020","unstructured":"Song YJ, Li SR, Li XW, Chen X, Wei ZX, Liu QS et al (2020) The effect of estrogen replacement therapy on Alzheimer\u2019s disease and Parkinson\u2019s disease in postmenopausal women: a meta-analysis. Front Neurosci 14:157. https:\/\/doi.org\/10.3389\/fnins.2020.00157","journal-title":"Front Neurosci"},{"key":"2922_CR41","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.bcp.2018.01.038","volume":"150","author":"A Szabo","year":"2018","unstructured":"Szabo A, Sumegi K, Fekete K, Hocsak E, Debreceni B, Setalo G Jr. et al (2018) Activation of mitochondrial fusion provides a new treatment for mitochondria-related diseases. Biochem Pharmacol 150:86\u201396. https:\/\/doi.org\/10.1016\/j.bcp.2018.01.038","journal-title":"Biochem Pharmacol"},{"key":"2922_CR42","doi-asserted-by":"publisher","first-page":"347","DOI":"10.2165\/00002512-199914050-00003","volume":"14","author":"A Tavani","year":"1999","unstructured":"Tavani A, La Vecchia C (1999) The adverse effects of hormone replacement therapy. Drugs Aging 14:347\u2013357. https:\/\/doi.org\/10.2165\/00002512-199914050-00003","journal-title":"Drugs Aging"},{"key":"2922_CR43","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.jns.2014.10.013","volume":"347","author":"M Tazir","year":"2014","unstructured":"Tazir M, Hamadouche T, Nouioua S, Mathis S, Vallat JM (2014) Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update. J Neurol Sci 347:14\u201322. https:\/\/doi.org\/10.1016\/j.jns.2014.10.013","journal-title":"J Neurol Sci"},{"key":"2922_CR44","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1038\/ng.3878","volume":"49","author":"IA Tchasovnikarova","year":"2017","unstructured":"Tchasovnikarova IA, Timms RT, Douse CH, Roberts RC, Dougan G, Kingston RE et al (2017) Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2. Nat Genet 49:1035\u20131044. https:\/\/doi.org\/10.1038\/ng.3878","journal-title":"Nat Genet"},{"key":"2922_CR45","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.cell.2021.10.029","volume":"185","author":"SG Varadarajan","year":"2022","unstructured":"Varadarajan SG, Hunyara JL, Hamilton NR, Kolodkin AL, Huberman AD (2022) Central nervous system regeneration. Cell 185:77\u201394. https:\/\/doi.org\/10.1016\/j.cell.2021.10.029","journal-title":"Cell"},{"key":"2922_CR46","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1080\/15548627.2019.1659609","volume":"16","author":"F Yang","year":"2020","unstructured":"Yang F, Xie HY, Yang LF, Zhang L, Zhang FL, Liu HY et al (2020) Stabilization of MORC2 by estrogen and antiestrogens through GPER1- PRKACA-CMA pathway contributes to estrogen-induced proliferation and endocrine resistance of breast cancer cells. Autophagy 16:1061\u20131076. https:\/\/doi.org\/10.1080\/15548627.2019.1659609","journal-title":"Autophagy"},{"key":"2922_CR47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017540","volume":"6","author":"SH Yuan","year":"2011","unstructured":"Yuan SH, Martin J, Elia J, Flippin J, Paramban RI, Hefferan MP et al (2011) Cell-surface marker signatures for the isolation of neural stem cells, glia and neurons derived from human pluripotent stem cells. PLoS ONE 6:e17540. https:\/\/doi.org\/10.1371\/journal.pone.0017540","journal-title":"PLoS ONE"},{"key":"2922_CR48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054059","volume":"8","author":"LV Yuzefovych","year":"2013","unstructured":"Yuzefovych LV, Musiyenko SI, Wilson GL, Rachek LI (2013) Mitochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice. PLoS ONE 8:e54059. https:\/\/doi.org\/10.1371\/journal.pone.0054059","journal-title":"PLoS ONE"},{"key":"2922_CR49","doi-asserted-by":"publisher","first-page":"8502","DOI":"10.1093\/nar\/gkz545","volume":"47","author":"L Zhang","year":"2019","unstructured":"Zhang L, Li DQ (2019) MORC2 regulates DNA damage response through a PARP1-dependent pathway. Nucleic Acids Res 47:8502\u20138520. https:\/\/doi.org\/10.1093\/nar\/gkz545","journal-title":"Nucleic Acids Res"},{"key":"2922_CR50","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.gendis.2023.05.010","volume":"11","author":"S Zhang","year":"2024","unstructured":"Zhang S, Guo A, Wang H, Liu J, Dong C, Ren J et al (2024) Oncogenic MORC2 in cancer development and beyond. Genes Dis 11:861\u2013873. https:\/\/doi.org\/10.1016\/j.gendis.2023.05.010","journal-title":"Genes Dis"},{"key":"2922_CR51","doi-asserted-by":"publisher","first-page":"17065","DOI":"10.1021\/ja1071114","volume":"132","author":"BS Zhao","year":"2010","unstructured":"Zhao BS, Liang Y, Song Y, Zheng C, Hao Z, Chen PR (2010) A highly selective fluorescent probe for visualization of organic hydroperoxides in living cells. J Am Chem Soc 132:17065\u201317067. https:\/\/doi.org\/10.1021\/ja1071114","journal-title":"J Am Chem Soc"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-025-02922-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00401-025-02922-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-025-02922-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T16:41:04Z","timestamp":1757349664000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00401-025-02922-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,4]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2922"],"URL":"https:\/\/doi.org\/10.1007\/s00401-025-02922-2","relation":{},"ISSN":["1432-0533"],"issn-type":[{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,4]]},"assertion":[{"value":"15 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"GSL, BOC and SCY filed a provisional patent based on this work.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Seoul National University (Approval No. SNU-241108\u20136). This study involved members of a family harboring MORC2 variants, including two clinically affected individuals. Written informed consent was obtained from all participants prior to enrollment. The study protocol was approved by the Institutional Review Board of Samsung Medical Center, Sungkyunkwan University (IRB No. 2014\u201308-057\u2013002).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participation"}},{"value":"All authors have read the final version of the manuscript and approved it for publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"13"}}