Comparing effects of microgravity and amyotrophic lateral sclerosis in the mouse ventral lumbar spinal cord

Yoshikawa, Masaaki; Ishikawa, Chihiro; Li, Haiyan; Kudo, Takashi; Shiba, Dai; Shimizu, Masaki; Murtani, Masafumi; Takahashi, Satoru; Aizawa, Shin; Shiga, Takashi

doi:10.1016/j.mcn.2022.103745

Cited by 7 publications

(8 citation statements)

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“…3.7 Gene expression related to Imoonglia, macrophage, and satellite glial cells was affected in microgravity-exposed and SOD1 G93A mice Immune and glial cell-related gene expression was altered in the spinal cord of MG-exposed and SOD1 G93A mice (Yoshikawa et al, 2022b). To decipher the various effects of exposure to MG and ALS pathology on immune and glial cells in the DRG microenvironment,…”

Section: Gene Expression Related To Lowthreshold Mechanoreceptive And...mentioning

confidence: 99%

“…Microgravity (MG) exposure and amyotrophic lateral sclerosis (ALS) are characterized by common alterations in the skeletal muscle, motor, nervous, vasculature, and immune systems, leading to motor deficits, including muscle atrophy and loss of neuronal activity (Vinsant et al, 2013a;Vinsant et al, 2013b;Clément and Wood, 2014;Rizzo et al, 2014;Gunes et al, 2020;Yu et al, 2020;Buoite Stella et al, 2021;Okada et al, 2021;Yoshikawa et al, 2022a;Yoshikawa et al, 2022b). Exercise on the ground can reverse motor neuron and muscle abnormalities caused by exposure to MG, whereas the degeneration in ALS is irreversible and motor neuron death cannot be recovered.…”

Section: Introductionmentioning

confidence: 99%

“…Changes in gravity alter the sensory input from the vestibular system, which consequently generates mismatches between the expected and actual sensory vestibular inputs during active movements (Carriot et al, 2021). Furthermore, studies have shown that exposure to MG induces changes in structures and neuronal gene expressions in the brain and spinal cord (Carriot et al, 2021;Yoshikawa et al, 2022b;Holley et al, 2022;Mammarella et al, 2022). However, the alterations occurring in the sensorimotor system due to gravitational changes and the adaptation of sensory neurons during spaceflight have not been fully unraveled nor have the molecular mechanisms underlying these effects.…”

Section: Introductionmentioning

confidence: 99%

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Comparing the effects of microgravity and amyotrophic lateral sclerosis on mouse dorsal root ganglia

Yoshikawa

Matsukawa

Oshima

et al. 2023

Front. Space Technol.

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Introduction: Microgravity (MG) exposure causes motor deficits and decreased neuronal activity, effects that resemble the ones observed in motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Several recent studies have shown that exposure to MG and ALS also impacts the sensory systems. Yet, the role of sensory impairment in this degenerative process of exposure to MG and ALS remains unknown. In this study, we aimed at elucidating how the sensory system is affected by exposure to MG and ALS.Methods: To this end, we compared gene expression in the mouse lumbar dorsal root ganglia (DRG) of MG-exposed animals with that of control animals that remained under artificial gravity conditions. We then investigated the effects of the human superoxide dismutase 1 (SOD1) G93A mutation in a mouse model of ALS (SOD1G93A mice) on gene expression in the DRG.Results: The overlap of genes with negatively correlated expression was greater than those with positively correlated expression between the DRG of MG-exposed and SOD1G93A mice. Additionally, genes related to Imoonglia (characteristics of both immune and glial cells) and macrophage increased in response to MG exposure, while satellite glial cell genes were expressed in response to SOD1 mutation. Next, we examined genes related to sensory neuron subtypes in the DRG. We found altered gene expression in genes related to proprioceptive and mechanoreceptive neurons in the DRG of MG-exposed and SOD1G93A mice. Remarkably, the expression of Atf3 and genes related to nociceptive neurons in the DRG of SOD1G93A mice at postnatal day (P) 120 was considerably altered, whereas MG-exposed and SOD1G93A mice at P30 presented little changes.Discussion: These results indicate that exposure to MG and ALS affect gene expression in genes related to neurons and non-neuronal cells in the DRG, with significant differences between the effects of MG and the SOD1 mutation. Elucidation of the impact of exposure to MG and ALS pathogenesis in the DRG, including identification of the molecular pathways that regulate DRG dysfunction, will help better understand the differences in vulnerability and the triggering processes of impaired motor function associated with MG and ALS.

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Section: Gene Expression Related To Lowthreshold Mechanoreceptive And...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparing the effects of microgravity and amyotrophic lateral sclerosis on mouse dorsal root ganglia

Yoshikawa

Matsukawa

Oshima

et al. 2023

Front. Space Technol.

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“…One possible example is Amyotrophic Lateral Sclerosis (ALS) since both microgravity exposure and ALS are associated with significant motor abnormalities, exhibiting similarities in the degradation of the spinal cord, genetic markers, and pathogenesis. [13][14][15] Similarly, microgravity and space cause a cognition deficit due to accelerated neurodegeneration centered around a combination of oxidative stress and mitochondrial dysfunction leading to increased inflammation, 16 oxidative species-induced protein misfolding, and plaque buildup, 8,16 microgravity-induced neuropathy 1 mimicking Alzheimer's Disease (AD).Neuroinflammation Targets for Multiple Neurodegenerative Diseases. The NASA twin study documented the spaceflight-induced low-grade upregulation in inflammatory cytokines, shortened telomeres, and other attributes of accelerated aging, 7 resembling characteristics of "inflammaging".…”

mentioning

confidence: 99%

“…21,[23][24][25][26][27][28][29][30][31][32][33] As a result, microgravity and space environment appears to stress cells in ways that cause them to rapidly develop disease pathology that mimics debilitating motor and cognitive neurodegenerative diseases like AD and ALS. 1,8,[13][14][15] Due to the large number of potential targets involved, a high-throughput and targeted screening method is required to identify the best therapeutic target.…”

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confidence: 99%

Inflammasome-Inhibiting Nanoligomers are Neuroprotective Against Space-Induced Pathology in Healthy and Diseased 3D Human Motor and Pre-Frontal Cortex Brain Organoids

Sharma,

Gilberto,

Rask

et al. 2024

Preprint

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Microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to space astronauts and tourists, and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here we show, a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station (ISS). First, comparing 3D healthy and diseased pre-frontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimers Disease (AD), Frontotemporal Dementia (FTD), and Amyotrophic Lateral Sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 which targeted NF-κB, and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated Tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel, and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.

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Potential role of long noncoding RNA maternally expressed gene 3 (MEG3) in the process of neurodegeneration

Baazaoui,

Y. Alfaifi,

Ben Saad

et al. 2025

Neuroscience

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Comparing effects of microgravity and amyotrophic lateral sclerosis in the mouse ventral lumbar spinal cord

Cited by 7 publications

References 93 publications

Comparing the effects of microgravity and amyotrophic lateral sclerosis on mouse dorsal root ganglia

Comparing the effects of microgravity and amyotrophic lateral sclerosis on mouse dorsal root ganglia

Inflammasome-Inhibiting Nanoligomers are Neuroprotective Against Space-Induced Pathology in Healthy and Diseased 3D Human Motor and Pre-Frontal Cortex Brain Organoids

Potential role of long noncoding RNA maternally expressed gene 3 (MEG3) in the process of neurodegeneration

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