scholarly journals Fatal neuroinvasion of SARS-CoV-2 in K18-hACE2 mice is partially dependent on hACE2 expression

2021 ◽  
Author(s):  
Mariano Carossino ◽  
Paige Montanaro ◽  
Aoife O’Connell ◽  
Devin Kenney ◽  
Hans Gertje ◽  
...  
Keyword(s):  
Mouse Model ◽  
Motor Neurons ◽  
Neuronal Damage ◽  
Virus Transport ◽  
Cytokeratin 18 ◽  
Angiotensin Converting Enzyme 2 ◽  
Distinctive Features ◽  
Spinal Motor Neurons ◽  
Olfactory Neuroepithelium ◽  
Neuronal Disease

ABSTRACTAnimal models recapitulating the distinctive features of severe COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. However, the cause(s) and mechanisms of lethality in this mouse model remain unclear. Here, we evaluated the spatiotemporal dynamics of SARS-CoV-2 infection for up to 14 days post-infection. Despite infection and moderate inflammation in the lungs, lethality was invariably associated with viral neuroinvasion and neuronal damage (including spinal motor neurons). Neuroinvasion occurred following virus transport through the olfactory neuroepithelium in a manner that was only partially dependent on hACE2. Interestingly, SARS-CoV-2 tropism was overall neither widespread among nor restricted to only ACE2-expressing cells. Although our work incites caution in the utility of the K18-hACE2 model to study global aspects of SARS-CoV-2 pathogenesis, it underscores this model as a unique platform for exploring the mechanisms of SARS-CoV-2 neuropathogenesis.SUMMARYCOVID-19 is a respiratory disease caused by SARS-CoV-2, a betacoronavirus. Here, we show that in a widely used transgenic mouse model of COVID-19, lethality is invariably associated with viral neuroinvasion and the ensuing neuronal disease, while lung inflammation remains moderate.

Impaired hypoxic sensor Siah-1, PHD3, and FIH system in spinal motor neurons of an amyotrophic lateral sclerosis mouse model

2012 ◽  
Vol 91 (2) ◽  
pp. 285-291
Author(s):  
Kota Sato ◽  
Nobutoshi Morimoto ◽  
Tomoko Kurata ◽  
Takafumi Mimoto ◽  
Kazunori Miyazaki ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Motor Neurons ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Lateral Sclerosis

AIF translocates to the nucleus in the spinal motor neurons in a mouse model of ALS

2006 ◽  
Vol 406 (3) ◽  
pp. 205-210 ◽  
Author(s):  
Yeo Kyoung Oh ◽  
Ki Soon Shin ◽  
Shin Jung Kang
Keyword(s):  
Mouse Model ◽  
Motor Neurons ◽  
Spinal Motor Neurons ◽  
Spinal Motor

scholarly journals Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

2019 ◽  
Author(s):  
Christine Marques ◽  
Mathieu Fischer ◽  
Céline Keime ◽  
Thibaut Burg ◽  
Aurore Brunet ◽  
...  
Keyword(s):  
Mouse Model ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Rna Metabolism ◽  
Initiation Site ◽  
Spinal Motor Neurons ◽  
Adult Mice ◽  
End Stage ◽  
Neuronal Functions ◽  
Potential Initiation

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease clinically defined as the combined degeneration of corticospinal and corticobulbar neurons (CSN), and bulbar and spinal motor neurons (MN). A growing body of evidence points to the motor cortex, where CSN are located, as the potential initiation site of ALS. However, little is known about the spatiotemporal dynamics of CSN degeneration and the molecular pathways involved. Here, we show in the Sod1G86R mouse model of ALS that CSN loss precedes MN degeneration and that CSN and MN degenerations are somatotopically related, highlighting the relevance of CSN to ALS onset and progression. To gain insights into the molecular mechanisms that selectively trigger CSN degeneration, we purified CSN from the motor and somatosensory cortex of adult mice and analysed their transcriptome from presymptomatic ages to disease end-stage. Significant RNA metabolism and splicing alterations, novel in the context of Sod1 mutation, were identified, including mis-splicing events that largely trigger genes involved in neuronal functions. Together, the data indicate that CSN dysfunction and degeneration upon mutant Sod1 expression involve alterations of RNA metabolism and splicing, emphasizing shared mechanisms across various ALS-related genes.

Prevention and Healing of Calcium Signaling Mediated Neuronal Damage on successive Administration of Flavonoid Enriched Pterocarpus Marsupium Roxb in Peripheral Neuropathy Model

2020 ◽  
Vol 16 (9) ◽  
pp. 1346-1355
Author(s):  
Neethi Shaju ◽  
Mrinmoy Gautam ◽  
Abdul Khayum ◽  
Gunasekaran Venkatesh
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Sciatic Nerve ◽  
Motor Neurons ◽  
Neuronal Damage ◽  
Interleukin 10 ◽  
Central Mechanism ◽  
Behavioral Models ◽  
Cell Hyperplasia ◽  
Pterocarpus Marsupium

Background: Modern research on peripheral neuropathy circumstance utter that treatments with Vincristine (VCR) disturb the microtubular cells in sensory and motor neurons due to calcium over- load in sciatic nerve, unfortunately, VCR triggering the release of Tumor necrosis factor-α (TNFα) in central neurons causes excitotoxicity as well. Although ethnomedical information specifies that Pterocarpus marsupium Roxb (PM) is widely used for various nervous disorders, not yet justified on VCR induced peripheral neuropathy and in relation to central mechanism. Objective: This study is aimed to explore the possible central and peripheral mechanism of flavonoid enriched PM in VCR induced neuropathy model. Methods: Neuropathic pain was induced in female Wistar rats by VCR (75μg/ kg/day, i.p) for 10 days. Nociceptive thresholds were assessed by subjecting them to behavioral and biochemical estimation, proinflammatory cytokines along with morphological evaluation. Results: PM significantly increased the nociceptive threshold evident from various behavioral models in comparison to VCR group. More importantly, PM significantly reversed the VCR induced calcium elevation, glutamate and aspartate release in the brain. Discussion: It was also observed that the raised TNF-α, Interleukin-1β were controlled and interleukin- 10 was elevated in sciatic nerve after PM treatment. Evident from histology, PM markedly reversed the VCR induced axonal degeneration, Schwann cell hyperplasia, and myelin fibrosis. Conclusion: Flavonoid enriched PM both 100 & 200mg/kg post and co-administration exerted a preventive and curative effect in VCR induced neuropathic pain by controlling calcium-mediated excitotoxicity through peripheral and central mechanism.

scholarly journals Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Michael D. Sunshine ◽  
Antonino M. Cassarà ◽  
Esra Neufeld ◽  
Nir Grossman ◽  
Thomas H. Mareci ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Neurons ◽  
Drug Overdose ◽  
Cervical Spinal Cord ◽  
Opioid Overdose ◽  
Electrode Position ◽  
Spinal Motor Neurons ◽  
Cord Injury ◽  
Low Amplitude

AbstractRespiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.

scholarly journals The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

2020 ◽  
Author(s):  
Paymaan Jafar-nejad ◽  
Berit Powers ◽  
Armand Soriano ◽  
Hien Zhao ◽  
Daniel A Norris ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Cell Types ◽  
Rnase H ◽  
Central Administration ◽  
Spinal Motor Neurons ◽  
New Class ◽  
Wide Range ◽  
Therapeutic Development

Abstract Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

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