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Current Protein & Peptide Science 2023Multiple sclerosis (MS) is an autoimmune disorder that affects the central nervous system (CNS), including the brain, spinal cord, and optic nerves. The symptoms can... (Review)
Review
Multiple sclerosis (MS) is an autoimmune disorder that affects the central nervous system (CNS), including the brain, spinal cord, and optic nerves. The symptoms can vary from muscle weakness to vision loss. In the case of MS, the immune system attacks the myelin sheath, which protects the nerve fiber and causes inflammation resulting in demyelination. The myelin sheath has the composition of various proteins including membrane proteins and glycoproteins. The four main proteins namely Myelin Basic Protein (MBP), Myelin associated Oligodendrocyte Basic protein (MOBP), Myelin Proteolipid Protein (PLP) and Myelin Associated Glycoprotein (MAG) are known to be critical auto-antigens in causing demyelination in CNS leading to MS. Three out of these four proteins are intrinsically disordered proteins and in this review, we attempted to understand how these proteins play a crucial role in maintaining the integrity of myelin, by exploring its structural and functional aspects and also their auto-antigenicity leading to multiple sclerosis.
Topics: Humans; Multiple Sclerosis; Myelin Proteins; Central Nervous System; Autoimmune Diseases; Spinal Cord; Antigens
PubMed: 37461348
DOI: 10.2174/1389203724666230717124101 -
Nature Communications Oct 2023Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia...
Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8 T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.
Topics: Animals; Mice; Axons; CD8-Positive T-Lymphocytes; Demyelinating Diseases; Microglia; Myelin Sheath; Neuroinflammatory Diseases
PubMed: 37903797
DOI: 10.1038/s41467-023-42570-2 -
ELife May 2023The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a...
The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near-complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are likely due to a combination of increased activity level and sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca ATPase (SERCA) activity and energy dissipation. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle and hyperactivity. This serendipitous discovery provides proof-of-concept that sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can be harnessed to promote energy expenditure and metabolic health.
Topics: Mice; Humans; Animals; Muscle, Skeletal; Thermogenesis; Energy Metabolism; Proteolipids; Cytoplasm; Chromosomes, Human; Calcium
PubMed: 37249575
DOI: 10.7554/eLife.86023 -
Journal of Integrative Plant Biology Jan 2020Cell polarity plays an important role in a wide range of biological processes in plant growth and development. Cell polarity is manifested as the asymmetric distribution... (Review)
Review
Cell polarity plays an important role in a wide range of biological processes in plant growth and development. Cell polarity is manifested as the asymmetric distribution of molecules, for example, proteins and lipids, at the plasma membrane and/or inside of a cell. Here, we summarize a few polarized proteins that have been characterized in plants and we review recent advances towards understanding the molecular mechanism for them to polarize at the plasma membrane. Multiple mechanisms, including membrane trafficking, cytoskeletal activities, and protein phosphorylation, and so forth define the polarized plasma membrane domains. Recent discoveries suggest that the polar positioning of the proteo-lipid membrane domain may instruct the formation of polarity complexes in plants. In this review, we highlight the factors and regulators for their functions in establishing the membrane asymmetries in plant development. Furthermore, we discuss a few outstanding questions to be addressed to better understand the mechanisms by which cell polarity is regulated in plants.
Topics: Cell Membrane; Cell Polarity; Homeostasis; Plant Cells; Plant Proteins; Plants
PubMed: 31889400
DOI: 10.1111/jipb.12904 -
Proceedings of the National Academy of... Oct 2022Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported...
Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1α) signaling as the use of an IRE1α inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1α signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis.
Topics: Alveolar Epithelial Cells; Endoplasmic Reticulum Stress; Endoribonucleases; Inositol; Lung Injury; Protein Serine-Threonine Kinases; Proteostasis; Pulmonary Fibrosis; Membrane Proteins; Cellular Reprogramming; Pulmonary Surfactant-Associated Protein C
PubMed: 36252035
DOI: 10.1073/pnas.2123187119 -
Journal of Translational Autoimmunity 2020Multiple sclerosis (MS) is widely acknowledged to be an autoimmune disease affecting the neuronal myelin structure of the CNS. Autoantigens recognized as the target of... (Review)
Review
Multiple sclerosis (MS) is widely acknowledged to be an autoimmune disease affecting the neuronal myelin structure of the CNS. Autoantigens recognized as the target of this autoimmune process are: myelin basal protein, anti-proteolipid protein, antimyelin-associated glycoprotein and antimyelin-based oligodendrocytic basic protein. Ample evidence supports the idea of a dysregulation of immunological tolerance towards self-antigens of neuronal myelin structure triggered by one or more viral or bacterial microbial agents in predisposed HLA gene subjects. Genetic predisposition to MS has been highlighted by numerous studies associating the disease to specific HLA haplotypes. Moreover, a wide range of evidence supports the fact that MS may be consequence of one or more viral or bacterial infections such as measles virus, EBV, HHV6, HZV, Chlamydia pneumoniae, Helicobacter Pylori, and other microbial agents. Microbiota elements also seems to have a role on the determinism of the disease as a pathogenic or protective factor. The autoimmune pathogenetic process could arise when a molecular mimicry between a foreign microbial antigen and an auto-antigen occurs in an HLA gene subject competent for that particular antigen. The antigen-presenting cells in this case would induce the activation of a specific Th clone causing a cross-reaction between a foreign antigen and an autoantigen resulting in an autoimmune response.
PubMed: 32743522
DOI: 10.1016/j.jtauto.2020.100039 -
Glia Sep 2023Schwann cells (SCs) form myelin and provide metabolic support for axons, and are essential for normal nerve function. Identification of key molecules specific to SCs and...
Schwann cells (SCs) form myelin and provide metabolic support for axons, and are essential for normal nerve function. Identification of key molecules specific to SCs and nerve fibers may provide new therapeutic targets for diabetic peripheral neuropathy (DPN). Argonaute2 (Ago2) is a key molecular player that mediates the activity of miRNA-guided mRNA cleavage and miRNA stability. Our study found that Ago2 knockout (Ago2-KO) in proteolipid protein (PLP) lineage SCs in mice resulted in a significant reduction of nerve conduction velocities and impairments of thermal and mechanical sensitivities. Histopathological data revealed that Ago2-KO significantly induced demyelination and neurodegeneration. When DPN was induced in both wild-type and Ago2-KO mice, Ago2-KO mice exhibited further decreased myelin thickness and exacerbated neurological outcomes compared with wild-type mice. Deep sequencing analysis of Ago2 immunoprecipitated complexes showed that deregulated miR-206 in Ago2-KO mice is highly related to mitochondrial function. In vitro data showed that knockdown of miR-200 induced mitochondrial dysfunction and apoptosis in SCs. Together, our data suggest that Ago2 in SCs is essential to maintain peripheral nerve function while ablation of Ago2 in SCs exacerbates SC dysfunction and neuronal degeneration in DPN. These findings provide new insight into the molecular mechanisms of DPN.
Topics: Mice; Animals; Diabetic Neuropathies; Schwann Cells; Myelin Sheath; Axons; MicroRNAs; Diabetes Mellitus
PubMed: 37178056
DOI: 10.1002/glia.24387 -
European Journal of Paediatric... Nov 2022The clinical spectrum of Pelizaeus-Merzbacher disease (PMD), a common hypomyelinating leukodystrophy, ranges between severe neonatal onset and a relatively stable...
BACKGROUND
The clinical spectrum of Pelizaeus-Merzbacher disease (PMD), a common hypomyelinating leukodystrophy, ranges between severe neonatal onset and a relatively stable presentation with later onset and mainly lower limb spasticity. In view of emerging treatment options and in order to grade severity and progression, we developed a PMD myelination score.
METHODS
Myelination was scored in 15 anatomic sites (items) on conventional T2-and T1w images in controls (n = 328) and 28 PMD patients (53 MRI; n = 5 connatal, n = 3 transitional, n = 10 classic, n = 3 intermediate, n = 2 PLP0, n = 3 SPG2, n = 2 female). Items included in the score were selected based on interrater variability, practicability of scoring and importance of scoring items for discrimination between patients and controls and between patient subgroups. Bicaudate ratio, maximal sagittal pons diameter, and visual assessment of midsagittal corpus callosum were separately recorded.
RESULTS
The resulting myelination score consisting of 8 T2-and 5 T1-items differentiates patients and controls as well as patient subgroups at first MRI. There was very little myelin and early loss in severely affected connatal and transitional patients, more, though still severely deficient myelin in classic PMD, ongoing myelination during childhood in classic and intermediate PMD. Atrophy, present in 50% of patients, increased with age at imaging.
CONCLUSIONS
The proposed myelination score allows stratification of PMD patients and standardized assessment of follow-up. Loss of myelin in severely affected and PLP0 patients and progressing myelination in classic and intermediate PMD must be considered when evaluating treatment efficacy.
Topics: Infant, Newborn; Humans; Female; Pelizaeus-Merzbacher Disease; Myelin Proteolipid Protein; Mutation; Magnetic Resonance Imaging; Corpus Callosum
PubMed: 36368233
DOI: 10.1016/j.ejpn.2022.10.003 -
Molecular Biology 2021The mechanisms involved in the origin and development of malignant and neurodegenerative diseases are an important area of modern biomedicine. A crucial task is to...
The mechanisms involved in the origin and development of malignant and neurodegenerative diseases are an important area of modern biomedicine. A crucial task is to identify new molecular markers that are associated with rearrangements of intracellular signaling and can be used for prognosis and the development of effective treatment approaches. The proteolipid plasmolipin (PLLP) is a possible marker. PLLP is a main component of the myelin sheath and plays an important role in the development and normal function of the nervous system. PLLP is involved in intracellular transport, lipid raft formation, and Notch signaling. PLLP is presumably involved in various disorders, such as cancer, schizophrenia, Alzheimer's disease, and type 2 diabetes mellitus. PLLP and its homologs were identified as possible virus entry receptors. The review summarizes the data on the PLLP structure, normal functions, and role in diseases.
PubMed: 34955555
DOI: 10.1134/S0026893321050113 -
ELife May 2022Human myelin disorders are commonly studied in mouse models. Since both clades evolutionarily diverged approximately 85 million years ago, it is critical to know to what...
Human myelin disorders are commonly studied in mouse models. Since both clades evolutionarily diverged approximately 85 million years ago, it is critical to know to what extent the myelin protein composition has remained similar. Here, we use quantitative proteomics to analyze myelin purified from human white matter and find that the relative abundance of the structural myelin proteins PLP, MBP, CNP, and SEPTIN8 correlates well with that in C57Bl/6N mice. Conversely, multiple other proteins were identified exclusively or predominantly in human or mouse myelin. This is exemplified by peripheral myelin protein 2 (PMP2), which was specific to human central nervous system myelin, while tetraspanin-2 (TSPAN2) and connexin-29 (CX29/GJC3) were confined to mouse myelin. Assessing published scRNA-seq-datasets, human and mouse oligodendrocytes display well-correlating transcriptome profiles but divergent expression of distinct genes, including and . A searchable web interface is accessible via www.mpinat.mpg.de/myelin. Species-dependent diversity of oligodendroglial mRNA expression and myelin protein composition can be informative when translating from mouse models to humans.
Topics: Animals; Connexins; Humans; Mice; Mice, Inbred Strains; Myelin Proteins; Myelin Proteolipid Protein; Myelin Sheath; Nerve Tissue Proteins; Oligodendroglia; Proteome; Tetraspanins; Transcriptome
PubMed: 35543322
DOI: 10.7554/eLife.77019