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1.
Phys Rev E ; 104(2-1): 024417, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1393562

ABSTRACT

In several pathological conditions, such as coronavirus infections, multiple sclerosis, Alzheimer's and Parkinson's diseases, the physiological shape of axons is altered and a periodic sequence of bulges appears. Experimental evidences suggest that such morphological changes are caused by the disruption of the microtubules composing the cytoskeleton of the axon. In this paper, we develop a mathematical model of damaged axons based on the theory of continuum mechanics and nonlinear elasticity. The axon is described as a cylinder composed of an inner passive part, called axoplasm, and an outer active cortex, composed mainly of F-actin and able to contract thanks to myosin-II motors. Through a linear stability analysis we show that, as the shear modulus of the axoplasm diminishes due to the disruption of the cytoskeleton, the active contraction of the cortex makes the cylindrical configuration unstable to axisymmetric perturbations, leading to a beading pattern. Finally, the nonlinear evolution of the bifurcated branches is investigated through finite element simulations.


Subject(s)
Axons/pathology , Elasticity , Models, Neurological , Actins/metabolism , Axons/metabolism , Biomechanical Phenomena
2.
J Biol Chem ; 295(20): 6926-6935, 2020 05 15.
Article in English | MEDLINE | ID: covidwho-830746

ABSTRACT

Mouse hepatitis virus (MHV; murine coronavirus) causes meningoencephalitis, myelitis, and optic neuritis followed by axonal loss and demyelination. This murine virus is used as a common model to study acute and chronic virus-induced demyelination in the central nervous system. Studies with recombinant MHV strains that differ in the gene encoding the spike protein have demonstrated that the spike has a role in MHV pathogenesis and retrograde axonal transport. Fusion peptides (FPs) in the spike protein play a key role in MHV pathogenesis. In a previous study of the effect of deleting a single proline residue in the FP of a demyelinating MHV strain, we found that two central, consecutive prolines are important for cell-cell fusion and pathogenesis. The dihedral fluctuation of the FP was shown to be repressed whenever two consecutive prolines were present, in contrast to the presence of a single proline in the chain. Using this proline-deleted MHV strain, here we investigated whether intracranial injection of this strain can induce optic neuritis by retrograde axonal transport from the brain to the retina through the optic nerve. We observed that the proline-deleted recombinant MHV strain is restricted to the optic nerve, is unable to translocate to the retina, and causes only minimal demyelination and no neuronal death. We conclude that an intact proline dyad in the FP of the recombinant demyelinating MHV strain plays a crucial role in translocation of the virus through axons and subsequent neurodegeneration.


Subject(s)
Axonal Transport/genetics , Murine hepatitis virus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Animals , Axonal Transport/physiology , Axons/metabolism , Axons/virology , Brain/metabolism , Coronavirus Infections/pathology , Demyelinating Diseases/metabolism , Male , Mice , Mice, Inbred C57BL , Murine hepatitis virus/metabolism , Optic Nerve/metabolism , Optic Nerve/virology , Peptides/metabolism , Proline/metabolism , Sequence Deletion/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins/metabolism
3.
J Virol ; 94(14)2020 07 01.
Article in English | MEDLINE | ID: covidwho-823496

ABSTRACT

Mouse hepatitis virus (MHV) is a murine betacoronavirus (m-CoV) that causes a wide range of diseases in mice and rats, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the central nervous system (CNS). MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus-induced neural-cell damage leading to demyelination and axonal loss, which are pathological features of multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia, and their interplay are the primary pathophysiological events leading to disruption of the myelin sheath in MS. However, there is emerging evidence supporting gray matter involvement and degeneration in MS. The investigation of T cell function in the pathogenesis of deep gray matter damage is necessary. Here, we employed RSA59 (an isogenic recombinant strain of MHV-A59)-induced experimental neuroinflammation model to compare the disease in CD4-/- mice with that in CD4+/+ mice at days 5, 10, 15, and 30 postinfection (p.i.). Viral titer estimation, nucleocapsid gene amplification, and viral antinucleocapsid staining confirmed enhanced replication of the virions in the absence of functional CD4+ T cells in the brain. Histopathological analyses showed elevated susceptibility of CD4-/- mice to axonal degeneration in the CNS, with augmented progression of acute poliomyelitis and dorsal root ganglionic inflammation rarely observed in CD4+/+ mice. Depletion of CD4+ T cells showed unique pathological bulbar vacuolation in the brain parenchyma of infected mice with persistent CD11b+ microglia/macrophages in the inflamed regions on day 30 p.i. In summary, the current study suggests that CD4+ T cells are critical for controlling acute-stage poliomyelitis (gray matter inflammation), chronic axonal degeneration, and inflammatory demyelination due to loss of protective antiviral host immunity.IMPORTANCE The current trend in CNS disease biology is to attempt to understand the neural-cell-immune interaction to investigate the underlying mechanism of neuroinflammation, rather than focusing on peripheral immune activation. Most studies in MS are targeted toward understanding the involvement of CNS white matter. However, the importance of gray matter damage has become critical in understanding the long-term progressive neurological disorder. Our study highlights the importance of CD4+ T cells in safeguarding neurons against axonal blebbing and poliomyelitis from murine betacoronavirus-induced neuroinflammation. Current knowledge of the mechanisms that lead to gray matter damage in MS is limited, because the most widely used animal model, experimental autoimmune encephalomyelitis (EAE), does not present this aspect of the disease. Our results, therefore, add to the existing limited knowledge in the field. We also show that the microglia, though important for the initiation of neuroinflammation, cannot establish a protective host immune response without the help of CD4+ T cells.


Subject(s)
Axons/immunology , Axons/metabolism , CD4 Antigens/deficiency , Coronavirus Infections/immunology , Coronavirus Infections/virology , Murine hepatitis virus/physiology , Poliomyelitis/etiology , Animals , Axons/pathology , Brain/immunology , Brain/metabolism , Brain/pathology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Coronavirus Infections/pathology , Cytokines/metabolism , Disease Models, Animal , Disease Susceptibility/immunology , Ganglia, Spinal/immunology , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , Immunohistochemistry , Inflammation Mediators/metabolism , Mice
4.
Am J Hum Genet ; 107(4): 763-777, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-758482

ABSTRACT

Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.


Subject(s)
Axons/metabolism , Charcot-Marie-Tooth Disease/genetics , Guanine Nucleotide Exchange Factors/genetics , Muscle Weakness/genetics , Muscular Atrophy, Spinal/genetics , Musculoskeletal Abnormalities/genetics , Adult , Aged , Aged, 80 and over , Amino Acid Sequence , Animals , Axons/pathology , COP-Coated Vesicles/metabolism , COP-Coated Vesicles/pathology , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/metabolism , Charcot-Marie-Tooth Disease/pathology , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Gene Expression , Golgi Apparatus/metabolism , Golgi Apparatus/pathology , Guanine Nucleotide Exchange Factors/metabolism , Heterozygote , Humans , Male , Mice , Middle Aged , Mitochondria/metabolism , Mitochondria/pathology , Motor Neurons/metabolism , Motor Neurons/pathology , Muscle Weakness/diagnosis , Muscle Weakness/metabolism , Muscle Weakness/pathology , Muscular Atrophy, Spinal/diagnosis , Muscular Atrophy, Spinal/metabolism , Muscular Atrophy, Spinal/pathology , Musculoskeletal Abnormalities/diagnosis , Musculoskeletal Abnormalities/metabolism , Musculoskeletal Abnormalities/pathology , Mutation , Pedigree , Primary Cell Culture , Spinal Cord/abnormalities , Spinal Cord/metabolism
5.
ACS Chem Neurosci ; 11(13): 1868-1870, 2020 07 01.
Article in English | MEDLINE | ID: covidwho-606648

ABSTRACT

Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Cytokines/metabolism , Pneumonia, Viral/metabolism , Solitary Nucleus/metabolism , Axons/immunology , Axons/metabolism , Axons/virology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/immunology , Cranial Nerves/immunology , Cranial Nerves/metabolism , Cranial Nerves/virology , Cytokines/immunology , Humans , Hypothalamo-Hypophyseal System/immunology , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/virology , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Pandemics , Pituitary-Adrenal System/immunology , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/virology , Pneumonia, Viral/immunology , SARS-CoV-2 , Solitary Nucleus/immunology , Solitary Nucleus/virology
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