TY - JOUR
T1 - Acquired expression of mutant mitofusin 2 causes progressive neurodegeneration and abnormal behavior
AU - Ishikawa, Kaori
AU - Yamamoto, Satoshi
AU - Hattori, Satoko
AU - Nishimura, Naoya
AU - Tani, Haruna
AU - Mito, Takayuki
AU - Matsumoto, Hirokazu
AU - Miyakawa, Tsuyoshi
AU - Nakada, Kazuto
N1 - Funding Information:
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), AMED-CREST (18gm1110006 to K.N.) from the Japan Agency for Medical Research and Development (AMED), 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 (http://www.editage.jp) have proofread and edited the paper. We thank 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; and the technical experts of the Division of SystemMedical Science, Institute for Comprehensive Medical Science, Fujita Health University, for their kind cooperation on our behavioral analyses. Behavioral analysis was performed 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.
Funding Information:
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), AMED-CREST (18gm1110006 to K.N.) from the Japan Agency for Medical Research and Development (AMED), 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 (http://www.editage.jp) have proofread and edited the paper. We thank 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) mouseline;andthetechnicalexpertsoftheDivisionofSystemMedicalScience,InstituteforComprehensiveMedical Science, Fujita Health University, for their kind cooperation on our behavioral analyses. Behavioral analysis was
Publisher Copyright:
© 2019 the authors.
PY - 2019/2/27
Y1 - 2019/2/27
N2 - 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 d after mutant expression during adulthood. After this silent 150 d 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.
AB - 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 d after mutant expression during adulthood. After this silent 150 d 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.
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U2 - 10.1523/JNEUROSCI.2139-18.2018
DO - 10.1523/JNEUROSCI.2139-18.2018
M3 - Article
C2 - 30606759
AN - SCOPUS:85062283517
VL - 39
SP - 1588
EP - 1604
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 9
ER -