Myelinated nerve fibres in the CNS

Hildebrand, Claes; Remahl, S.; Persson, Håkan; Bjartmar, Carl

doi:10.1016/0301-0082(93)90015-k

Cited by 332 publications

(265 citation statements)

References 344 publications

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“…6 B). Paranodal distribution of lysosomal constituents in normal myelinated nerves has been described previously (Hildebrand et al, 1992). Inhibition of lysosomal degradation by chloroquine treatment before immunostaining augmented the intracellular staining of PMP22 in Tr J /ϩ nerves (data not shown) (see also Fig.…”

Section: Most Of the Steady-state Pmp22 Protein Undergoes Complex Glysupporting

confidence: 70%

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

1997

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A nonconservative leucine to proline mutation in peripheral myelin protein 22 (PMP22) causes the Trembler-J (Tr J ) neuropathy in mice and humans. The expression levels and localization of the PMP22 protein in the Tr J mouse have not been previously determined. The aim of our studies was to reevaluate the extent of myelin deficit in genotyped heterozygous and homozygous animals and to examine how the Tr J mutation alters the normal in vivo post-translational processing of PMP22. Morphological studies show evidence for primary dysmyelination and myelin instability in affected animals. As expected, Western blot analysis indicates that in adult heterozygous Tr J animals, the level of PMP22 is markedly decreased, similar to myelin basic protein and protein zero, whereas myelin-associated glycoprotein is largely unaffected. The decrease in myelin protein expression is associated with an increase in lysosomal biogenesis, suggestive of augmented endocytosis or autophagy. Double-immunolabeling experiments show the accumulation of PMP22 in endosomal/lysosomal structures of Tr J Schwann cells, and chloroquine treatment of nerve segments indicates that the degradation of protein zero, PMP22, and myelin basic protein is augmented in Tr J nerves. These studies suggest that the Tr J mutation alters myelin stability and that the mutant protein is likely degraded via the lysosomal pathway. Key words: peripheral myelin protein 22; Schwann cells; peripheral nervous system; myelin; neuropathy; Trembler-J; endosomal-lysosomal pathway; protein processingThe Trembler (Tr) and Trembler-J (Tr J ) mice are animal models for the human hereditary neuropathy Charcot-Marie-Tooth (CMT) disease, a group of common (1/2500) (Skre, 1974) heterogeneous peripheral neuropathies. In mice, the semidominant and dominantly inherited mutations in the pmp22 gene result in the nonconservative leucine-to-proline (L16P) or glycine-toaspartic acid (G160D) replacements in the PMP22 protein in the Tr J or Tr mouse, respectively (Suter et al., 1992a,b). These mutations are believed to be responsible for the PNS deficits. The majority of human patients with CMT, however, do not have point mutations in the PMP22 gene, but instead harbor a submicroscopic chromosomal duplication on human chromosome 17p11.2-12, which encompasses the PMP22 gene (for review, see Suter and Snipes, 1995a). The similarity of the disease phenotypes, including disease progression, as well as the finding of the identical Tr J single point mutation in a severely affected CMT disease type 1A (CMT1A) family (Valentijn et al., 1992) substantiates the use of these mice as models of human disease and provide a system for elucidating the biology of the PMP22 protein.The ways in which pmp22 mutations perturb myelination are complex, particularly because the function of the PMP22 protein is unknown (for review, see Suter and Snipes, 1995b). Previous morphological studies of the Tr J mouse used the close linkage of the Tr J phenotype to the vestigial tail marker on mouse chromosome 11 to predict the ...

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Section: Most Of the Steady-state Pmp22 Protein Undergoes Complex Glysupporting

confidence: 70%

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

1997

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“…The myelin sheath is therefore crucial to normal neurological function, and the density of myelinated axons is commonly used to assess the relative maturity of brain regions. Traditionally, histological studies of myelin growth have been qualitative, making direct ontogenetic comparisons between species difficult (5,6,(30)(31)(32)(33)(34)(35)(36)(37). Nonetheless, previous studies (5, 6) described greater initial myelination of the cerebral cortex in neonatal macaque monkeys compared with humans.…”

Section: Discussionmentioning

confidence: 99%

Prolonged myelination in human neocortical evolution

Miller

Duka

Stimpson

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

559

454

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Nerve myelination facilitates saltatory action potential conduction and exhibits spatiotemporal variation during development associated with the acquisition of behavioral and cognitive maturity. Although human cognitive development is unique, it is not known whether the ontogenetic progression of myelination in the human neocortex is evolutionarily exceptional. In this study, we quantified myelinated axon fiber length density and the expression of myelinrelated proteins throughout postnatal life in the somatosensory (areas 3b/3a/1/2), motor (area 4), frontopolar (prefrontal area 10), and visual (areas 17/18) neocortex of chimpanzees (N = 20) and humans (N = 33). Our examination revealed that neocortical myelination is developmentally protracted in humans compared with chimpanzees. In chimpanzees, the density of myelinated axons increased steadily until adult-like levels were achieved at approximately the time of sexual maturity. In contrast, humans displayed slower myelination during childhood, characterized by a delayed period of maturation that extended beyond late adolescence. This comparative research contributes evidence crucial to understanding the evolution of human cognition and behavior, which arises from the unfolding of nervous system development within the context of an enriched cultural environment. Perturbations of normal developmental processes and the decreased expression of myelin-related molecules have been related to psychiatric disorders such as schizophrenia. Thus, these species differences suggest that the human-specific shift in the timing of cortical maturation during adolescence may have implications for vulnerability to certain psychiatric disorders.C omparative studies suggest that human neurobiological development is unique. For example, humans differ from other primates in extending a rapid, fetal-like brain mass growth rate into the first postnatal year, thereby achieving relatively large adult brain size (1). Gene expression patterns related to postnatal development of the prefrontal cortex are delayed in humans compared with chimpanzees and macaque monkeys (2). In addition, synapse maturation (3, 4) and axon myelination (5, 6) occur during later life history stages in humans compared with macaques. Furthermore, recent volumetric data obtained by using in vivo MRI demonstrates that human neural development and aging differ from those of our close nonhuman primate relatives (7-9). Together, these observations indicate that a marked delay in the developmental schedule of human neocortex may play an important role in the growth of connections that contribute to our species-specific cognitive abilities by providing greater opportunities for social learning to influence the establishment of circuits.

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“…Myelin membrane components are metabolically relatively stable with half-lives on the order of several weeks to months 2,3 . Nevertheless, protein/lipid turnover is, in general, necessary to replace potentially impaired molecules with new functional copies in order to combat functional decline [4][5][6][7] . How do molecules trapped within the numerous layers of tightly compacted membrane enter the degradative system?…”

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confidence: 99%

Age-related myelin degradation burdens the clearance function of microglia during aging

Kannaiyan²,

et al. 2016

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2Myelin is synthesized as a multilamellar membrane, but the mechanisms of membrane turnover are unknown. We find that myelin pieces are gradually released from aging myelin sheaths and are subsequently cleared by microglia. Myelin fragmentation increases with age and leads to the formation of insoluble, lipofuscin-like lysosomal inclusions in microglia. Thus, age-related myelin fragmentation is substantial leading to lysosomal storage and contributing to microglia senescence and immune dysfunction in aging.Myelin is formed by oligodendrocytes as a multilamellar structure that encloses segments of axons in the central nervous systems (CNS) of vertebrates 1 . Once myelin is laid down, it is unknown to what extent the sheaths require maintenance and remodeling. Membrane turnover may pose a problem for oligodendrocytes that form up to 80 different myelin sheaths of tightly stacked membrane, but harbour little cytoplasm and few lysosomes, the organelles responsible for membrane degradation. Myelin membrane components are metabolically relatively stable with half-lives on the order of several weeks to months 2,3 . Nevertheless, protein/lipid turnover is, in general, necessary to replace potentially impaired molecules with new functional copies in order to combat functional decline [4][5][6][7] . How do molecules trapped within the numerous layers of tightly compacted membrane enter the degradative system? We tested the hypothesis that myelin degradation occurs in part via shedding of myelin fragments into the extracellular space.We analyzed the white matter of aging mice (up to 24 months) by electron microscopy to search for myelin breakdown products. We detected multilamellar myelin fragments more frequently in the brain of the older mice, of which some were associated with myelin sheaths, while others were in the extracellular space or inside of cells (Supplementary Fig. 1). As fixation artefacts frequently affect the appearance of myelin in chemically fixed tissue, we used high-pressure freezing to fix tissue and confirmed the progressive accumulation of multilamellar myelin fragments with age ( Fig. 1a,b).Since some of these myelin fragments were found inside cells, we performed immunhistochemistry to determine whether microglia, the brain phagocytes [8][9][10] , were responsible for the uptake of myelin fragments. An increasing number of myelin basic protein (MBP) and proteolipid protein (PLP) immunoreactive puncta co-localized with Iba1-positive microglia with age ( Fig. 1c, Supplementary Fig. 1).Three-dimensional reconstructions demonstrated that immunoreactive puncta were present inside of microglia (Fig. 1c). Since our results suggested that microglia clear away the myelin fragments that accumulate in the 3 aging brain, we compared microglia number and appearance in young and old animals. Not only had the number of microglia increased in the white matter of old animals as reported previously 11,12 , but also microglia in contact with myelin ( Supplementary Fig. 2). Next, the morphology of lysosomes was evalua...

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Myelinated nerve fibres in the CNS

Cited by 332 publications

References 344 publications

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

Prolonged myelination in human neocortical evolution

Age-related myelin degradation burdens the clearance function of microglia during aging

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