ALS Under the Microscope: Immune Cells, Genetics, and the Quest for Answer

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons in the spinal cord and brain. Patients with ALS have a disability to voluntary control of limbs and even trouble with breathing. Unfortunately, there is no cure for this disorder. One of the decisions is hiding in several types of immune cells that are the human organism’s defenders. First, scientists have focused on microglia, the ever-vigilant residential central nervous system macrophages. These cells play a crucial role in maintaining brain and spinal cord homeostasis and providing phagocytosis, eliminating injured neurons or debris. Microglia functions in ALS are not straightforward but rather complex and multifaceted, posing significant challenges to scientists understanding. The activated microglia are highly heterogeneous cells with a lot of subpopulations regulated by genetic background and all other related genes that may interact with the gene of interest. However, the impact of genetic background on the precise roles of specific forms of microglia and their interactions with other forms of immune cells in driving pathological mechanisms in ALS remains unclear.

The investigation into the impact of genetic background variations on microglia heterogeneity and functions in mice models of ALS was a collaborative effort led by Dr. Okiru Komine and Professor Koji Yamanaka from Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine (RIEM), Nagoya University with their team. This team, which included Professor Tomoo Ogi from Department of Genetics, RIEM, Naogya University and Associate Professor Kunihiko Hinohara from Department of Immunology, Naogya University Graduate School of Medicine, has made significant strides in understanding the pathological nature of ALS. Their collective effort underscores the importance of collaboration in advancing the knowledge of neurodegenerative diseases.

This groundbreaking article, published in iScience, is the first to unveil the profound impact of genetic background variation on microglial heterogeneity in two distinct ALS model mice. The research, conducted with meticulous methods such as behavioral, molecular, cell biology, and genetic techniques, including single-cell RNA sequencing analysis, has brought to light novel insights into the effects of genetic diversity on microglial subpopulations in ALS. The detailed single-cell RNA sequencing analysis has revealed microglial heterogeneity in twelve gene expression groups, significantly advancing our understanding of ALS pathology.

Professor Koji Yamanaka explains, “The mice models with a mutation in the gene coding special enzyme superoxide dismutase 1 used in the study of ALS are the best choice to investigate not only the heterogeneity of microglia but also the impact of T-lymphocytes, other immune cells infiltrated to the spinal cord and impact on disease-associated microglia (DAM) genes.” He continues, “Our research affirms the correlation between microglia heterogeneity and the systemic immune environment in albino and black ALS model mice. Moreover, we identified elevated expression levels of neuroprotective genes, suggesting the presence of a subset of genes in the black mice models that could potentially confer a neuroprotective effect against the progression of ALS.” The understanding of how to defend motor neurons during ALS is one of the clues to the disease treatment.

The research further declares differences in the numbers of infiltrating immune cells and the ratios of peripheral immune cells between black and albino mice models at the end-stage of the disease. Some DAM gene markers exhibited opposite regulation between microglia from black and albino mice. “Based on our present and previous studies, we suggest that environmental factors from peripheral immune cells and/or infiltrating immune cells may influence disease progression by modulating survival and DAM induction in ALS model mice,” highlights Dr. Okiru Komine.  In conclusion, the extensive research conducted by Dr. Okiru Komine, Professor Koji Yamanaka, and their highly qualified team has unveiled the significant impact of genetic background variation on microglial heterogeneity, their responses, and disease progression in ALS model mice. However, as the experiments were limited to only two strains, the team emphasized the necessity for further analysis involving ALS model mice with diverse genetic backgrounds. This is crucial to comprehensively understand the underlying mechanisms and pave the way for potential treatments.

JOURNAL REFERENCE

Okiru Komine, Syuhei Ohnuma, Kunihiko Hinohara, Yuichiro Hara, Mayuko Shimada, Tomohiro Akashi, Seiji Watanabe, Akira Sobue, Noe Kawade, Tomoo Ogi and Koji Yamanaka. “Genetic background variation impacts microglial heterogeneity and disease progression in amyotrophic lateral sclerosis model mice”. iScience 27 (2024) 108872.

DOI: https://doi.org/10.1016/j.isci.2024.108872.

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