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

• Published in: The Journal of neuroscience Vol. 39; no. 9; pp. 1588 - 1604
• Main Authors: Ishikawa, Kaori, Yamamoto, Satoshi, Hattori, Satoko, Nishimura, Naoya, Tani, Haruna, Mito, Takayuki, Matsumoto, Hirokazu, Miyakawa, Tsuyoshi, Nakada, Kazuto
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 27.02.2019
• Subjects: Abnormalities; Animals; Brain - growth & development; Brain - metabolism; Brain - pathology; Brain damage; Brain injury; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - pathology; Charcot-Marie-Tooth Disease - physiopathology; Dependence; Developmental plasticity; Disease Models, Animal; Gene Knock-In Techniques - standards; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Humans; Learning; Lethal effects; Mice; Mice, Inbred C57BL; Mimicry; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mutation, Missense; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neurons; Neurons - metabolism; Neurons - pathology; MFN2; cognitive impairment; hyperactivity; progressive neurodegeneration; mitochondrial dynamics
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.2139-18.2018

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 ( ). 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. 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 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.