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Acquired Expression of Mutant Mitofusin 2 Causes Progressive Neurodegeneration and Abnormal Behavior

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Acquired Expression of Mutant Mitofusin 2 Causes Progressive Neurodegeneration and Abnormal Behavior This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. A link to any extended data will be provided when the final version is posted online. Research Articles: Cellular/Molecular Acquired expression of mutant Mitofusin 2 causes progressive neurodegeneration and abnormal behavior Kaori Ishikawa1,2, Satoshi Yamamoto3, Satoko Hattori4, Naoya Nishimura3, Takayuki Mito1, Hirokazu Matsumoto3, Tsuyoshi Miyakawa4 and Kazuto Nakada1,2 1Faculty of Life and Environmental Sciences, University of Tsukuba. 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8572, Japan. 2Graduate School of Life and Environmental Sciences, University of Tsukuba. 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8572, Japan. 3Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd. 26-1, 2-chome, Muraoka-Higashi, Fujisawa, Kanagawa, 251-8555, Japan. 4Division of System Medical Science, Institute for Comprehensive Medical Science, Fujita Health University. 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. https://doi.org/10.1523/JNEUROSCI.2139-18.2018 Received: 20 August 2018 Revised: 3 December 2018 Accepted: 17 December 2018 Published: 3 January 2019 Author contributions: K.i., S.Y., and S.H. designed research; K.i., S.Y., N.N., and H.T. performed research; K.i., S.Y., and N.N. contributed unpublished reagents/analytic tools; K.i., S.H., and T. Mito analyzed data; K.i. wrote the first draft of the paper; K.i., S.Y., S.H., H.M., T. Miyakawa, and K.N. edited the paper; K.i. wrote the paper. Conflict of Interest: S.Y., N.N., and H.M. were full-time employees of Takeda Pharmaceutical Company Ltd. at the time of this study. We are grateful to all Tg/KO group members of the Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd. for generating the CamK2a-tTA/TRE-hMFN2(D210V) mouse line. Behavioral analysis was carried out at Institute for Comprehensive Medical Science, Fujita Health University (Joint Usage/Research Center for Genes, Brain and Behavior accredited by Minister of Education, Culture, Sports, Science and Technology) in Japan. We also thank the technical experts of the Division of System Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, for their kind cooperation on our behavioral analyses. This work was supported by Grants-in-Aid for Young Scientists B [16K18535 to K.I.], Scientific Research C [18K06203 to K.I.], Scientific Research B [16H04678 to K.N.], Challenging Exploratory Research [16K14719 to K.N.] from the Japan Society for the Promotion of Science (JSPS), Life Sciences Fellowships from Takeda Science Foundation to K.I., Grant-in-Aid for Scientific Research on Innovative Areas (Platform of Advanced Animal Model Support [16H06276 to T. Miyakawa]) from ministry of Education, culture, sports, science and technology (MEXT) in Japan. Two professional English-speaking editors from Editage (www.editage.jp) have proofread and edited the manuscript. Correspondence should be addressed: Kaori Ishikawa (Ph.D) and Kazuto Nakada (Ph.D), Faculty of Life and Environmental Sciences, University of Tsukuba., 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8572, Japan, [K.I.] Tel: +81-29-853-4653 | FAX: +81-29-853-6614, | Email: [email protected], [K.N.] Tel: +81-29-853-6694 | FAX: +81-29-853-6614, | Email: [email protected] Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.2139-18.2018 Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2019 the authors <Title> Acquired expression of mutant Mitofusin 2 causes progressive neurodegeneration and abnormal behavior <Abbreviated title> Mutant MFN2 causes progressive neurodegeneration <Authors> 1,2 3 4 3 Kaori Ishikawa *, Satoshi Yamamoto , Satoko Hattori , Naoya Nishimura , Takayuki 1 3 4 1,2 Mito , Hirokazu Matsumoto , Tsuyoshi Miyakawa , and Kazuto Nakada * <Affiliations> 1 Faculty of Life and Environmental Sciences, University of Tsukuba. 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8572, Japan. 2 Graduate School of Life and Environmental Sciences, University of Tsukuba. 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8572, Japan. 3 Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd. 26-1, 2-chome, Muraoka-Higashi, Fujisawa, Kanagawa, 251-8555, Japan. 4 Division of System Medical Science, Institute for Comprehensive Medical Science, Fujita Health University. 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. * Correspondence should be addressed Kaori Ishikawa (Ph.D) and Kazuto Nakada (Ph.D) Faculty of Life and Environmental Sciences, University of Tsukuba. 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8572, Japan [K.I.] Tel: +81-29-853-4653 | FAX: +81-29-853-6614 | Email: [email protected] [K.N.] Tel: +81-29-853-6694 | FAX: +81-29-853-6614 | Email: [email protected] Number of pages: 58 (including main figures), 49 (without figures) Number of figures: 9 main figures and 2 extended data Number of tables: 1 Number of words for <Abstract>: 144, <Introduction>: 631, <Discussion>: 1,476 <Conflict of Interests> S.Y., N.N., and H.M. were full-time employees of Takeda Pharmaceutical Company Ltd. at the time of this study. <Acknowledgements> We are grateful to all Tg/KO group members of the Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd. for generating the CamK2a-tTA/TRE-hMFN2(D210V) mouse line. Behavioral analysis was carried out at Institute for Comprehensive Medical Science, Fujita Health University (Joint Usage / Research Center for Genes, Brain and Behavior accredited by Minister of Education, Culture, Sports, Science and Technology) in Japan. We also thank the technical experts of the Division of System Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, for their kind cooperation on our behavioral analyses. This work was supported by Grants-in-Aid for Young Scientists B [16K18535 to K.I.], Scientific Research C [18K06203 to K.I.], Scientific Research B [16H04678 to K.N.], Challenging Exploratory Research [16K14719 to K.N.] from the Japan Society for the Promotion of Science (JSPS), Life Sciences Fellowships from Takeda Science Foundation to K.I., Grant-in-Aid for Scientific Research on Innovative Areas (Platform of Advanced Animal Model Support [16H06276 to T. Miyakawa]) from ministry of Education, culture, sports, science and technology (MEXT) in Japan. Two professional English-speaking editors from Editage (www.editage.jp) have proofread and edited the manuscript. <Author Contributions> K.I., S.Y., and S.H. designed the study. S.Y. and N.N. generated transgenic mice under H.M.’s supervision. K.I. conducted experiments under K.N.’s supervision. S.H. and T. Miyakawa supervised behavioral experiments. T. Mito advised on muscle pathology. K.I. wrote the initial draft of the manuscript. All authors contributed to the analysis and interpretation of data. All authors critically reviewed the content of the manuscript and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. <Abstract> Neurons have high plasticity in developmental and juvenile stages that decreases in adulthood. Mitochondrial dynamics are highly important in neurons to maintain normal function. To compare dependency on mitochondrial dynamics in juvenile and adult stages, we generated a mouse model capable of selective timing of the expression of a mutant of the mitochondrial fusion factor Mitofusin 2 (MFN2). Mutant expression in the juvenile stage had lethal effects. Contrastingly, abnormalities did not manifest until 150 days after mutant expression during adulthood. After this silent 150-day period, progressive neurodegeneration, abnormal behaviors, and learning and memory deficits similar to those seen in human neurodegenerative diseases were observed. This indicates that abnormal neuronal mitochondrial dynamics seriously affect survival during early life stages and can also significantly damage brain function after maturation. Our findings highlight the need to consider the timing of disease onset in mimicking human neurodegenerative diseases. <Significance Statement> To compare the dependency on mitochondrial dynamics in neurons in juvenile and adult stages, we generated a mouse model expressing a mutant of the mitochondrial fusion factor Mfn2 in an arbitrary timing. Juvenile expression of the mutant showed acute and severe phenotypes and had lethal effects, however, post-adult expression induced delayed but progressive phenotypes resembling those found in human neurodegenerative diseases. Our results indicate that abnormal neuronal mitochondrial dynamics seriously affect survival during early life stages and can also significantly damage brain function after maturation. This strongly suggests that the timing of expression should be considered when establishing an animal model that closely resembles human neurodegenerative diseases. <Keywords> Mitochondrial
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