Genetic background variation impacts microglial heterogeneity and disease progression in amyotrophic lateral sclerosis model mice
Okiru Komine,
Syuhei Ohnuma,
Kunihiko Hinohara,
Yuichiro Hara,
Mayuko Shimada,
Tomohiro Akashi,
Seiji Watanabe,
Akira Sobue,
Noe Kawade,
Tomoo Ogi,
Koji Yamanaka
Affiliations
Okiru Komine
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan; Department of Neuroscience and Pathobiology, Nagoya University Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan; Corresponding author
Syuhei Ohnuma
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan; Department of Neuroscience and Pathobiology, Nagoya University Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan
Kunihiko Hinohara
Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Institute for Advanced Research, Nagoya University, Nagoya, Aichi, Japan; Center for 5D Cell Dynamics, Nagoya University, Nagoya, Aichi, Japan
Yuichiro Hara
Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan; Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
Mayuko Shimada
Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan; Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
Tomohiro Akashi
Center for 5D Cell Dynamics, Nagoya University, Nagoya, Aichi, Japan; Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
Seiji Watanabe
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan; Department of Neuroscience and Pathobiology, Nagoya University Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan
Akira Sobue
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan; Department of Neuroscience and Pathobiology, Nagoya University Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan; Medical Interactive Research and Academia Industry Collaboration Center, Research Institute of Environmental Medicine, Nagoya University, Aichi, Japan
Noe Kawade
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan; Department of Neuroscience and Pathobiology, Nagoya University Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan
Tomoo Ogi
Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan; Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Institute for Glyco-core Research (iGCORE), Nagoya University, Aichi, Japan; Center for One Medicine Innovative Translational Research (COMIT), Nagoya University, Aichi, Japan
Koji Yamanaka
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan; Department of Neuroscience and Pathobiology, Nagoya University Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan; Institute for Glyco-core Research (iGCORE), Nagoya University, Aichi, Japan; Center for One Medicine Innovative Translational Research (COMIT), Nagoya University, Aichi, Japan; Corresponding author
Summary: Recent single-cell analyses have revealed the complexity of microglial heterogeneity in brain development, aging, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Disease-associated microglia (DAMs) have been identified in ALS mice model, but their role in ALS pathology remains unclear. The effect of genetic background variations on microglial heterogeneity and functions remains unknown. Herein, we established and analyzed two mice models of ALS with distinct genetic backgrounds of C57BL/6 and BALB/c. We observed that the change in genetic background from C57BL/6 to BALB/c affected microglial heterogeneity and ALS pathology and its progression, likely due to the defective induction of neurotrophic factor-secreting DAMs and impaired microglial survival. Single-cell analyses of ALS mice revealed new markers for each microglial subtype and a possible association between microglial heterogeneity and systemic immune environments. Thus, we highlighted the role of microglia in ALS pathology and importance of genetic background variations in modulating microglial functions.
