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Current Opinion in Pharmacology Oct 2022Amino acids and their derivatives function as building blocks as well as signaling molecules to modulate various cellular processes in living organisms. In mice, amino... (Review)
Review
Amino acids and their derivatives function as building blocks as well as signaling molecules to modulate various cellular processes in living organisms. In mice, amino acids accumulate in demyelinated lesions and return to basal levels during remyelination. Studies have found that amino acids and their metabolites modulate immune activity in the central nervous system (CNS) and influence oligodendrocyte differentiation and remyelination efficiency. In this review, we discuss current studies on amino acid metabolism in the context of CNS remyelination. By understanding the mechanisms of amino acid signaling and metabolism in demyelinated lesions, we may deepen our understanding of compartmentalized CNS inflammation in demyelinating disease like multiple sclerosis (MS) and provide evidence to develop novel pharmacological therapies targeting amino acid metabolism to prevent disease worsening.
Topics: Amino Acids; Animals; Central Nervous System; Demyelinating Diseases; Mice; Microglia; Multiple Sclerosis; Oligodendroglia; Remyelination
PubMed: 36067684
DOI: 10.1016/j.coph.2022.102287 -
Cancer Medicine Aug 2023Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult...
BACKGROUND
Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique.
METHODS
In this study, we extracted cell-free DNA from the CSF (CSF-cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet-digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease.
RESULTS
Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF-cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF-cfDNA detected MYD88 and CD79 mutations in 60% of CNSLs each, with either mutation detected in 80% of cases. Mutual existence of both mutations was identified in 40% of cases. These mutations were not detected in either infectious or demyelinating diseases, and the sensitivity and specificity of detecting either MYD88/CD79B mutations in CNSL were 80% and 100%, respectively. In the four cases biopsied, the median time from collecting CSF with the detected mutations to definitive diagnosis by conventional methods was 22.5 days (range, 18-93 days).
CONCLUSIONS
These results suggest that mutation analysis using CSF-cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform.
Topics: Humans; Myeloid Differentiation Factor 88; Central Nervous System Neoplasms; Lymphoma, Non-Hodgkin; Liquid Biopsy; Cell-Free Nucleic Acids; Communicable Diseases; Demyelinating Diseases
PubMed: 37501501
DOI: 10.1002/cam4.6329 -
Journal of Neuroinflammation Mar 2023Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the central nervous system (CNS). Although studies have demonstrated that microglia...
Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the central nervous system (CNS). Although studies have demonstrated that microglia facilitate remyelination in demyelinating diseases, the underlying mechanisms are still not fully characterized. We found that aryl hydrocarbon receptor (AhR), an environment sensor, was upregulated within the corpus callosum in the cuprizone model of CNS demyelination, and upregulated AhR was mainly confined to microglia. Deletion of AhR in adult microglia inhibited efficient remyelination. Transcriptome analysis using RNA-seq revealed that AhR-deficient microglia displayed impaired gene expression signatures associated with lysosome and phagocytotic pathways. Furthermore, AhR-deficient microglia showed impaired clearance of myelin debris and defected phagocytic capacity. Further investigation of target genes of AhR revealed that spleen tyrosine kinase (SYK) is the downstream effector of AhR and mediated the phagocytic capacity of microglia. Additionally, AhR deficiency in microglia aggravated CNS inflammation during demyelination. Altogether, our study highlights an essential role for AhR in microglial phagocytic function and suggests the therapeutic potential of AhR in demyelinating diseases.
Topics: Animals; Mice; Corpus Callosum; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice, Inbred C57BL; Microglia; Myelin Sheath; Receptors, Aryl Hydrocarbon; Remyelination
PubMed: 36966295
DOI: 10.1186/s12974-023-02764-3 -
Molecular Neurobiology Nov 2023Autosomal dominant leukodystrophy (ADLD) is an ultra-rare, slowly progressive, and fatal neurodegenerative disorder associated with the loss of white matter in the... (Review)
Review
Autosomal dominant leukodystrophy (ADLD) is an ultra-rare, slowly progressive, and fatal neurodegenerative disorder associated with the loss of white matter in the central nervous system (CNS). Several years after its first clinical description, ADLD was found to be caused by coding and non-coding variants in the LMNB1 gene that cause its overexpression in at least the brain of patients. LMNB1 encodes for Lamin B1, a protein of the nuclear lamina. Lamin B1 regulates many cellular processes such as DNA replication, chromatin organization, and senescence. However, its functions have not been fully characterized yet. Nevertheless, Lamin B1 together with the other lamins that constitute the nuclear lamina has firstly the key role of maintaining the nuclear structure. Being the nucleus a dynamic system subject to both biochemical and mechanical regulation, it is conceivable that changes to its structural homeostasis might translate into functional alterations. Under this light, this review aims at describing the pieces of evidence that to date have been obtained regarding the effects of LMNB1 overexpression on cellular morphology and functionality. Moreover, we suggest that further investigation on ADLD morpho-functional consequences is essential to better understand this complex disease and, possibly, other neurological disorders affecting CNS myelination.
Topics: Humans; Rare Diseases; Demyelinating Diseases; Brain; Lysosomal Storage Diseases; Neurodegenerative Diseases; Models, Theoretical
PubMed: 37450245
DOI: 10.1007/s12035-023-03461-1 -
Annals of Clinical and Translational... Jan 2020Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate...
OBJECTIVE
Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1-related disease, and to identify possible genotype-phenotype relationships.
METHODS
We performed a multinational cross-sectional survey among 20 patients with biallelic RARS1 variants identified by next-generation sequencing techniques. Clinical data, brain MRI findings and genetic results were analyzed. Additionally, ArgRS activity was measured in fibroblasts of four patients, and translation of long and short ArgRS isoforms was quantified by western blot.
RESULTS
Clinical presentation ranged from severe (onset in the first 3 months, usually with refractory epilepsy and early brain atrophy), to intermediate (onset in the first year with nystagmus and spasticity), and mild (onset around or after 12 months with minimal cognitive impairment and preserved independent walking). The most frequent RARS1 variant, c.5A>G, led to mild or intermediate phenotypes, whereas truncating variants and variants affecting amino acids close to the ArgRS active centre led to severe phenotypes. ArgRS activity was significantly reduced in three patients with intermediate and severe phenotypes; in a fourth patient with intermediate to severe presentation, we measured normal ArgRS activity, but found translation mainly of the short instead of the long ArgRS isoform.
INTERPRETATION
Variants in RARS1 impair ArgRS activity and do not only lead to a classic hypomyelination presentation with nystagmus and spasticity, but to a wide spectrum, ranging from severe, early-onset epileptic encephalopathy with brain atrophy to mild disease with relatively preserved myelination.
Topics: Adolescent; Adult; Age of Onset; Arginine-tRNA Ligase; Child; Child, Preschool; Cross-Sectional Studies; Genetic Association Studies; Hereditary Central Nervous System Demyelinating Diseases; Humans; Infant; Magnetic Resonance Imaging; Severity of Illness Index; Young Adult
PubMed: 31814314
DOI: 10.1002/acn3.50960 -
Virology Journal Mar 2023Multiple sclerosis (MS) is characterized by neuroinflammation and demyelination orchestrated by activated neuroglial cells, CNS infiltrating leukocytes, and their...
BACKGROUND
Multiple sclerosis (MS) is characterized by neuroinflammation and demyelination orchestrated by activated neuroglial cells, CNS infiltrating leukocytes, and their reciprocal interactions through inflammatory signals. An inflammatory stimulus triggers inducible nitric oxide synthase (NOS2), a pro-inflammatory marker of microglia/macrophages (MG/Mφ) to catalyze sustained nitric oxide production. NOS2 during neuroinflammation, has been associated with MS disease pathology; however, studies dissecting its role in demyelination are limited. We studied the role of NOS2 in a recombinant β-coronavirus-MHV-RSA59 induced neuroinflammation, an experimental animal model mimicking the pathological hallmarks of MS: neuroinflammatory demyelination and axonal degeneration.
OBJECTIVE
Understanding the role of NOS2 in murine-β-coronavirus-MHV-RSA59 demyelination.
METHODS
Brain and spinal cords from mock and RSA59 infected 4-5-week-old MHV-free C57BL/6 mice (WT) and NOS2-/- mice were harvested at different disease phases post infection (p.i.) (day 5/6-acute, day 9/10-acute-adaptive and day 30-chronic phase) and compared for pathological outcomes.
RESULTS
NOS2 was upregulated at the acute phase of RSA59-induced disease in WT mice and its deficiency resulted in severe disease and reduced survival at the acute-adaptive transition phase. Low survival in NOS2-/- mice was attributed to (i) high neuroinflammation resulting from increased accumulation of macrophages and neutrophils and (ii) Iba1 + phagocytic MG/Mφ mediated-early demyelination as observed at this phase. The phagocytic phenotype of CNS MG/Mφ was confirmed by significantly higher mRNA transcripts of phagocyte markers-CD206, TREM2, and Arg1 and double immunolabelling of Iba1 with MBP and PLP. Further, NOS2 deficiency led to exacerbated demyelination at the chronic phase as well.
CONCLUSION
Taken together the results imply that the immune system failed to control the disease progression in the absence of NOS2. Thus, our observations highlight a protective role of NOS2 in murine-β-coronavirus induced demyelination.
Topics: Animals; Mice; Demyelinating Diseases; Membrane Glycoproteins; Mice, Inbred C57BL; Murine hepatitis virus; Neuroinflammatory Diseases; Nitric Oxide Synthase Type II; Receptors, Immunologic; Coronavirus Infections
PubMed: 36966345
DOI: 10.1186/s12985-023-02006-1 -
Acta Neuropathologica Communications Mar 2021Cognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains...
Cognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains and hippocampal atrophy correlates with cognitive decline in MS patients. Cellular and molecular mechanisms responsible for neuronal dysfunction in demyelinated hippocampi are not fully understood. Here we investigate a mouse model of hippocampal demyelination where twelve weeks of treatment with the oligodendrocyte toxin, cuprizone, demyelinates over 90% of the hippocampus and causes decreased memory/learning. Long-term potentiation (LTP) of hippocampal CA1 pyramidal neurons is considered to be a major cellular readout of learning and memory in the mammalian brain. In acute slices, we establish that hippocampal demyelination abolishes LTP and excitatory post-synaptic potentials of CA1 neurons, while pre-synaptic function of Schaeffer collateral fibers is preserved. Demyelination also reduced Ca-mediated firing of hippocampal neurons in vivo. Using three-dimensional electron microscopy, we investigated the number, shape (mushroom, stubby, thin), and post-synaptic densities (PSDs) of dendritic spines that facilitate LTP. Hippocampal demyelination did not alter the number of dendritic spines. Surprisingly, dendritic spines appeared to be more mature in demyelinated hippocampi, with a significant increase in mushroom-shaped spines, more perforated PSDs, and more astrocyte participation in the tripartite synapse. RNA sequencing experiments identified 400 altered transcripts in demyelinated hippocampi. Gene transcripts that regulate myelination, synaptic signaling, astrocyte function, and innate immunity were altered in demyelinated hippocampi. Hippocampal remyelination rescued synaptic transmission, LTP, and the majority of gene transcript changes. We establish that CA1 neurons projecting demyelinated axons silence their dendritic spines and hibernate in a state that may protect the demyelinated axon and facilitates functional recovery following remyelination.
Topics: Animals; Astrocytes; Cognitive Dysfunction; Cuprizone; Demyelinating Diseases; Dendritic Spines; Disease Models, Animal; Hippocampus; Long-Term Potentiation; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron; Multiple Sclerosis; Neurons; Post-Synaptic Density; Sequence Analysis, RNA
PubMed: 33648591
DOI: 10.1186/s40478-021-01130-9 -
Neurologia I Neurochirurgia Polska 2022Multiple sclerosis (MS) is by far the most common central nervous system inflammatory demyelinating disease (CNS-IDD). It is diagnosed according to detailed criteria... (Review)
Review
Multiple sclerosis (MS) is by far the most common central nervous system inflammatory demyelinating disease (CNS-IDD). It is diagnosed according to detailed criteria based on clinical definitions, magnetic resonance imaging (MRI) and cerebrospinal fluid findings. However, in rare instances, atypical syndromes associated with CNS demyelination, such as unusual MRI findings or poor response to standard treatment, may eventually necessitate a CNS biopsy with neuropathological examination. Pathology remains the gold standard in the differentiation of atypical CNS-IDDs, the recognition of which is essential for establishing the correct prognosis and optimal therapy. However, one must bear in mind that between different CNS-IDDs there are still overlapping features, even in the pathology. In this review, we compare and highlight contrasts within a spectrum of CNS-IDDs from the neuropathological perspective. We characterise pathological hallmarks of active vs chronic multiple sclerosis. Also, we define differences in the pathology of MS, acute disseminated encephalomyelitis (ADEM), aquaporin 4-IgG positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOsd), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Detailed description of the particular CNS-IDD pathology is crucial on an individual patient level (when clinically justified in atypical cases) but also from a broader perspective i.e. to advance our understanding of the complex disease mechanisms. Recent immunobiological and pathological discoveries have led to the description of novel inflammatory CNS disorders that were previously classified as rare MS variants, such as NMOsd and MOGAD. Multiple sclerosis remains an umbrella diagnosis, as there is profound heterogeneity between patients. Advances in neuropathology research are likely to disentangle and define further CNS-IDDs that used to be categorised as multiple sclerosis.
Topics: Aquaporin 4; Autoantibodies; Central Nervous System; Central Nervous System Diseases; Humans; Immunoglobulin G; Multiple Sclerosis; Neuromyelitis Optica
PubMed: 35758517
DOI: 10.5603/PJNNS.a2022.0046 -
Annals of Clinical and Translational... Feb 2021To determine whether animals with Japanese macaque encephalomyelitis (JME), a spontaneous demyelinating disease similar to multiple sclerosis (MS), harbor...
OBJECTIVE
To determine whether animals with Japanese macaque encephalomyelitis (JME), a spontaneous demyelinating disease similar to multiple sclerosis (MS), harbor myelin-specific T cells in their central nervous system (CNS) and periphery.
METHODS
Mononuclear cells (MNCs) from CNS lesions, cervical lymph nodes (LNs) and peripheral blood of Japanese macaques (JMs) with JME, and cervical LN and blood MNCs from healthy controls or animals with non-JME conditions were analyzed for the presence of myelin-specific T cells and changes in interleukin 17 (IL-17) and interferon gamma (IFNγ) expression.
RESULTS
Demyelinating JME lesions contained CD4 T cells and CD8 T cells specific to myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and/or proteolipid protein (PLP). CD8 T-cell responses were absent in JME peripheral blood, and in age- and sex-matched controls. However, CD4 Th1 and Th17 responses were detected in JME peripheral blood versus controls. Cervical LN MNCs from eight of nine JME animals had CD3 T cells specific for MOG, MBP, and PLP that were not detected in controls. Mapping myelin epitopes revealed a heterogeneity in responses among JME animals. Comparison of myelin antigen sequences with those of JM rhadinovirus (JMRV), which is found in JME lesions, identified six viral open reading frames (ORFs) with similarities to myelin antigen sequences. Overlapping peptides to these JMRV ORFs did not induce IFNγ responses.
INTERPRETATIONS
JME possesses an immune-mediated component that involves both CD4 and CD8 T cells specific for myelin antigens. JME may shed new light on inflammatory demyelinating disease pathogenesis linked to gamma-herpesvirus infection.
Topics: Animals; Autoimmune Diseases; Demyelinating Diseases; Encephalomyelitis; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Epitopes; Female; Herpesviridae Infections; Interferon-gamma; Interleukin-17; Macaca fuscata; Male; Monkey Diseases; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Rhadinovirus; T-Lymphocytes
PubMed: 33440071
DOI: 10.1002/acn3.51303 -
Revista Medica Del Instituto Mexicano... Mar 2023Acute hemorrhagic leukoencephalitis (AHLE) is an inflammatory disease of the brain, with a fulminant course that leads to a hemorrhagic demyelination of the central... (Review)
Review
BACKGROUND
Acute hemorrhagic leukoencephalitis (AHLE) is an inflammatory disease of the brain, with a fulminant course that leads to a hemorrhagic demyelination of the central nervous system, having a poor prognosis and high mortality. Most of the times associated to crossed reactivity and molecular mimicry.
CLINICAL CASE
: We present a case report of a previously healthy young woman with an acute and multifocal clinical course, preceded by a viral respiratory tract infection, followed by a rapid disease progression and a delay in the diagnosis. The clinical, neuroimaging and cerebrospinal fluid featured suggested the diagnosis of AHLE, despite efforts and management with immunosuppression and intensive care, the response to treatment was poor leaving the patient with a severe neurological impairment.
CONCLUSION
There is little evidence regarding the clinical course and treatment of this disease, and more studies are needed to better characterize it and to provide further information about its prognosis and management. This paper gives a systematic review of the literature.
Topics: Female; Humans; Leukoencephalitis, Acute Hemorrhagic; Brain
PubMed: 37205605
DOI: No ID Found