Inherited Peripheral Neuropathies

The peripheral myelin protein-22 (PMP22) is a very hydrophobic glycoprotein and is highly expressed in compact PNS myelin. It has been mapped to the previously defined Tr locus on mouse chromosome 11. Comparison of marker genes on mouse chromosome 11 and human chromosome 17 revealed that PMP22 was also a candidate gene for the most common form of autosomal-dominant demyelinating hereditary peripheral neuropathy in humans, Charcot-Marie-Tooth disease type 1A (CMT1A). Indeed, the entire PMP22 gene is contained within a 1.5-Mb intrachromosomal duplication on chromosome 17p11.2, a genetic abnormality that had been linked to CMT1A by human molecular genetics. Consistent with these results, PMP22 is overexpressed in CMT1A patients who carry the characteristic duplication. The crucial role of PMP22 in the etiology of CMT1A was confirmed by generating transgenic mice and rats with increased PMP22 gene dosage, which resulted in severe PNS myelin deficits.

CMT is one of the more frequent hereditary diseases of the nervous system, with an overall prevalence of approximately 1 in 4000, and the CMT1A duplication accounts for around 70% of all cases. Why is this chromosomal abnormality so common? Detailed analysis of the CMT1A locus suggests that the duplication is due to crossing over involving repetitive sequences that flank the monomeric region. If correct, such a mechanism should also generate an allele carrying the reciprocal deletion of the same region. Indeed, the expected deletion is associated with the relatively mild recurrent neuropathy with liability to pressure palsy (HNPP). Thus, overexpression and underexpression of the myelin protein PMP22 are associated with myelin deficiencies in distinct human diseases. Although one might speculate from these data that correct stochiometry of myelin protein expression is crucial for a myelinating Schwann cell, the exact disease mechanism remains to be clarified.

Interestingly, the finding that a myelin protein was responsible for CMT1A led to the discovery that two other components of PNS myelin are mutated in rare forms of CMT1. The adhesion protein P0, which is largely responsible for PNS myelin compaction, is affected in CMT1B, and an X-linked form of CMT (CMTX) has been linked to mutations in the gap junction protein connexin-32. In contrast to PMP22 and P0, connexin-32 is located in uncompacted lamellae of PNS myelin, where it is thought to facilitate the exchange of small molecules via reflexive gap junctions between adaxonal and abaxonal aspects of myelinating Schwann cells.

Finally, there is a striking correlation between the role of PMP22 in the PNS and that of PLP/DM20 in the CNS with respect to biology and involvement in disease; both genes can be affected by various genetic mechanisms, including gene duplication and gene deletion. However, despite our vast knowledge derived from human molecular genetics, the molecular functions of both proteins are largely unknown. Given the recent findings that PMP22 and PLP/DM20 are members of extended gene families and may be involved in the control of cell proliferation and cell death, these proteins may have broader functions than simply being stabilizing building blocks of compact myelin.

In summary, the combination of basic and clinical sciences has led to substantial progress in the current understanding of common hereditary neuropathies. Using clinical, genetic, and cell biology approaches in concert, we will continue to learn more about disease mechanisms involved in neuropathies to the benefit of the clinic as much as to the understanding of myelin biology.

Ueli Suter

MBP+/MBP-) produces sufficient myelin to phenotyp-ically at least "cure" the shiverer of its overtly abnormal shivering behavior. These heterozygotes myelinate to a somewhat lesser extent than normal, but the fact that the shiverer phenotype is eliminated in the heterozygote even though the number of myelin sheaths around each axon is reduced indicates that there is a built-in safety factor in the normal situation.

Astrocytes Play Important Roles in CNS Homeostasis

As the name suggests, astrocytes are star-shaped process-bearing cells distributed throughout the central nervous system. They constitute from 20 to 50% of the volume of most brain areas. Astrocytes come in many shapes and forms. The two main forms, protoplasmic and fibrous astrocytes, predominate in gray and white matter, respectively (Fig. 1.16). Embryonically, astrocytes develop from radial glial cells, which transversely compartmentalize the neural tube. Radial glial cells serve as scaffolding for the migration of neurons and play a critical role in defining the cytoarchitecture of the CNS (Fig. 1.17). As the CNS matures, radial glia retract their processes and serve as progenitors of astrocytes. However, some specialized astrocytes of a radial nature are still found in the adult cerebellum and the retina and are known as Bergmann glial cells and Muller cells, respectively.

Astrocytes "fence in" neurons and oligodendrocytes (Arenander and de Vellis, 1983). The astrocytes achieve this isolation of the brain parenchyma by extending long processes projecting to the pia mater and the ependyma to form the glia limitans, by covering the surface of capillaries, and by making a cuff around the nodes of Ranvier. They also ensheath synapses and dendrites and project processes to cell somas (Fig. 1.18). Astrocytes are connected to each other by gap junctions, forming a syncytium that allows ions and small molecules to diffuse across the brain parenchyma. Astrocytes have in common unique cytological and immunological properties that make them easy to identify, including their star shape, the glial end feet on capillaries, and a unique population of large bundles of intermediate filaments. These filaments are composed of an astroglia-specific

Glia Limitans

FIGURE 1.17 Radial glia perform support and guidance functions for migrating neurons. In early development, the radial glia span the thickness of the expanding brain parenchyma. Inset: Defined layers of the neural tube from the ventricular to the outer surface: VZ, ventricular zone; IZ, intermediate zone; CP, cortical plate; MZ, marginal zone. The radial process of the glial cell is indicated in blue, and a single attached migrating neuron is depicted at the right.

FIGURE 1.17 Radial glia perform support and guidance functions for migrating neurons. In early development, the radial glia span the thickness of the expanding brain parenchyma. Inset: Defined layers of the neural tube from the ventricular to the outer surface: VZ, ventricular zone; IZ, intermediate zone; CP, cortical plate; MZ, marginal zone. The radial process of the glial cell is indicated in blue, and a single attached migrating neuron is depicted at the right.

Bergmann Glia Plp

Molecular layer

Purkinje cell layer

Granular layer

White matter

FIGURE 1.16 Arrangement of astrocytes in human cerebellar cortex. The Bergmann glial cells are in red, the protoplasmic astro-cytes are in green, and the fibrous astrocytes are in blue.

Molecular layer

Purkinje cell layer

Granular layer

White matter

FIGURE 1.16 Arrangement of astrocytes in human cerebellar cortex. The Bergmann glial cells are in red, the protoplasmic astro-cytes are in green, and the fibrous astrocytes are in blue.

Pia mater

FIGURE 1.18 Astrocytes (in orange) are depicted in situ in schematic relationship with other cell types with which they are known to interact. Astrocytes send processes that surround neurons and synapses, blood vessels, and the region of the node of Ranvier and extend to the ependyma as well as to the pia mater, where they form the glia limitans.

FIGURE 1.18 Astrocytes (in orange) are depicted in situ in schematic relationship with other cell types with which they are known to interact. Astrocytes send processes that surround neurons and synapses, blood vessels, and the region of the node of Ranvier and extend to the ependyma as well as to the pia mater, where they form the glia limitans.

protein commonly referred to as GFAP (glial fibrillary acidic protein). S-100, a calcium-binding protein, and glutamine synthetase also are astrocyte markers. Ultrastructurally, gap junctions (connexins), desmo-somes, glycogen granules, and membrane orthogonal arrays are distinct features used by morphologists to identify astrocytic cellular processes in the complex cytoarchitecture of the nervous system.

For a long time, astrocytes were thought to physically form the blood-brain barrier (considered later in this chapter), which prevents the entry of cells and diffusion of molecules into the CNS. In fact, astrocytes are indeed the blood-brain barrier in lower species. However, in higher species, the astrocytes are respon sible for inducing and maintaining the tight junctions in endothelial cells that effectively form the barrier (Goldstein, 1988; Raub et al, 1992). Astrocytes also take part in angiogenesis, which may be important in the development and repair of the CNS (Holash and Stewart, 1993). However, their role in this important process is still poorly understood.

Astrocytes Have a Wide Range of Functions

There is strong evidence for the role of radial glia and astrocytes in the migration and guidance of neurons in early development. Astrocytes are a major source of extracellular matrix proteins and adhesion molecules in the CNS; examples are nerve cell-nerve cell adhesion molecule (N-CAM), laminin, fibronectin, cytotactin, and the J-1 family members janusin and tenascin. These molecules participate not only in the migration of neurons, but also in the formation of neuronal aggregates, so-called nuclei, as well as networks.

Astrocytes produce, in vivo and in vitro, a very large number of growth factors. These factors act singly or in combination to selectively regulate the morphology, proliferation, differentiation, or survival, or all four, of distinct neuronal subpopulations. Most of the growth factors also act in a specific manner on the development and functions of astro-cytes and oligodendrocytes. The production of growth factors and cytokines by astrocytes and their responsiveness to these factors are a major mechanism underlying the developmental function and regenerative capacity of the CNS. During neurotransmission, neurotransmitters and ions are released at high concentrations in the synaptic cleft. The rapid removal of these substances is important so that they do not interfere with future synaptic activity. The presence of astrocyte processes around synapses positions them well to regulate neurotransmitter uptake and inactivation (Kettenman and Ransom, 1995). These possibilities are consistent with the presence in astrocytes of transport systems for many neu-rotransmitters. For instance, glutamate reuptake is performed mostly by astrocytes, which convert glutamate into glutamine and then release it into the extracellular space. Glutamine is taken up by neurons, which use it to generate glutamate and GABA, potent excitatory and inhibitory neurotransmitters, respectively (Fig. 1.19). Astrocytes contain ion channels for K+, Na+, Cl-, HCO-3, and Ca2+, as well as displaying a wide range of neurotransmitter receptors. K+ ions released from neurons during neurotransmission are soaked up by astrocytes and moved away from the area through astrocyte gap junctions. This is known

Glutamate Cycle

FIGURE 1.19 The glutamate-glutamine cycle is an example of a complex mechanism that involves an active coupling of neurotransmitter metabolism between neurons and astrocytes. The systems of exchange of glutamine, glutamate, GABA, and ammonia between neurons and astrocytes are highly integrated. The postulated detoxification of ammonia and inactivation of glutamate and GABA by astrocytes are consistent with the exclusive localization of glutamine synthetase in the astroglial compartment. Gln, glutamine.

FIGURE 1.19 The glutamate-glutamine cycle is an example of a complex mechanism that involves an active coupling of neurotransmitter metabolism between neurons and astrocytes. The systems of exchange of glutamine, glutamate, GABA, and ammonia between neurons and astrocytes are highly integrated. The postulated detoxification of ammonia and inactivation of glutamate and GABA by astrocytes are consistent with the exclusive localization of glutamine synthetase in the astroglial compartment. Gln, glutamine.

as "spatial buffering." The astrocytes play a major role in detoxification of the CNS by sequestering metals and a variety of neuroactive substances of endogenous and xenobiotic origin.

In response to stimuli, intracellular calcium waves are generated in astrocytes. The propagation of the Ca2+ wave can be visually observed as it moves across the cell soma and from astrocyte to astrocyte. The generation of Ca2+ waves from cell to cell is thought to be mediated by second messengers, diffusing through gap junctions (see Chapter 15). Because they develop postnatally in rodents, gap junctions may not play an important role in development. In the adult brain, gap junctions are present in all astrocytes. Some gap junctions have also been detected between astrocytes and neurons. Thus, they may participate, along with astroglial neurotransmitter receptors, in the coupling of astrocyte and neuron physiology.

In a variety of CNS disorders—neurotoxicity, viral infections, neurodegenerative disorders, HIV, AIDS, dementia, multiple sclerosis, inflammation, and trauma—astrocytes react by becoming hypertrophic and, in a few cases, hyperplastic. A rapid and huge upregulation of GFAP expression and filament formation is associated with astrogliosis. The formation of reactive astrocytes can spread very far from the site of origin. For instance, a localized trauma can recruit astrocytes from as far as the contralateral side, suggesting the existence of soluble factors in the mediation process. Tumor necrosis factor (TNF) and ciliary neurotrophic factors (CNTFs) have been identified as key factors in astrogliosis.

Microglia Are Mediators of Immune Responses in Nervous Tissue

The brain has traditionally been considered an "immunologically privileged site," mainly because the blood-brain barrier (see below) normally restricts the access of immune cells from the blood. However, it is now known that immunological reactions do take place in the central nervous system, particularly during cerebral inflammation. Microglial cells have been termed the tissue macrophages of the CNS, and they function as the resident representatives of the immune system in the brain. These cells are perhaps the least understood of the CNS cells. Although the function of microglia in the normal adult CNS remains to be clarified, a rapidly expanding literature describes microglia as major players in CNS development and in the pathogenesis of CNS disease. The notion that the CNS is an immune-privileged organ is no longer valid. A hallmark of microglial cells is their ability to become reactive and to respond to pathological challenges in a variety of ways.

The first description of microglial cells can be traced to Franz Nissl (1899) who used the term rod cell to describe a population of glial cells that reacted to brain pathology. He postulated that rod cell function was similar to that of leukocytes in other organs. Ramón y Cajal (1913) described microglia as part of his "third element" of the CNS—cells that he considered to be of mesodermal origin and distinct from neurons and astrocytes.

Del Rio-Hortega (1932) divided Ramón y Cajal's third element into oligodendrocytes and microglia, two cell types with different morphology, function, and origin. He used silver impregnation methods to visualize the ramified appearance of microglia in the adult brain, and he concluded that ramified microglia could transform into cells that were migratory, amoeboid, and phagocytic. A fundamental question raised by Del Rio-Hortega's studies was the origin of microglial cells. Although he provided evidence that microglia originated from cells that migrate into the brain from the pial surface, he also raised the possibility that microglia originate from blood "mononu-clears." Controversy over the lineage of microglia still exists today.

Microglia Have Diverse Functions in Developing and Mature Nervous Tissue

Four different sources of microglia have been proposed (Dolman, 1991): (1) bone marrow-derived monocytes, (2) mesodermal pial elements, (3) neural epidermal cells, and (4) capillary-associated pericytes.

On the basis of current knowledge, it appears that most ramified microglial cells are derived from bone marrow-derived monocytes, which enter the brain parenchyma during early stages of brain development. These cells help phagocytose degenerating cells that undergo programmed cell death as part of normal development. They retain the ability to divide and have the immunophenotypic properties of mono-cytes and macrophages. In addition to their role in remodeling the CNS during early development, microglia may secrete cytokines or growth factors that are important in fiber tract development, gliogenesis, and angiogenesis. After the early stages of development, amoeboid microglial cells transform into the ramified microglial cells that persist throughout adulthood (Altman, 1994).

Little is known about microglial function in the normal adult vertebrate CNS. Microglia constitute a formidable percentage (5-20%) of the total cells in the mouse brain. Microglia are found in all regions of the brain, and there are more in gray than in white matter. The phylogenetically newer regions of the CNS (cerebral cortex, hippocampus) have more microglia than do older regions (brainstem, cerebellum) (Lawson et al., 1990). Species variations also have been noted, as human white matter has three times more microglia than does rodent white matter.

Microglia usually have small rod-shaped somata from which numerous processes extend in a rather symmetrical fashion. Processes from different microglia rarely overlap or touch, and specialized contacts between microglia and other cells have not been described in the normal brain. Although each microglial cell occupies its own territory, microglia collectively form a network that covers much of the CNS parenchyma. Because of the numerous processes, microglia present extensive surface membrane to the CNS environment. Regional variation in the number and shape of microglia in the adult brain suggests that local environmental cues can affect microglial distribution and morphology. On the basis of these morphological observations, it is likely that microglia play a role in tissue homeostasis. The nature of this homeostasis remains to be elucidated. It is, however, clear that microglia can respond quickly and dramatically to alterations in the CNS microenvironment.

Microglia Become Activated in Pathological States

"Reactive" microglia can be distinguished from resting microglia by two criteria: (1) change in morphology and (2) upregulation of monocyte-

FIGURE 1.20 Activation of microglial cells in a tissue section from human brain. Resting microglia in normal brain (A). Activated microglia in diseased cerebral cortex (B) have thicker processes and larger cell bodies. In regions of frank pathology (C) microglia transform into phagocytic macrophages, which can also develop from circulating monocytes that enter the brain. Arrow in B indicates rod cell. Sections stained with antibody to ferritin. Bar = 40 |im.

Reactive Microglia

FIGURE 1.20 Activation of microglial cells in a tissue section from human brain. Resting microglia in normal brain (A). Activated microglia in diseased cerebral cortex (B) have thicker processes and larger cell bodies. In regions of frank pathology (C) microglia transform into phagocytic macrophages, which can also develop from circulating monocytes that enter the brain. Arrow in B indicates rod cell. Sections stained with antibody to ferritin. Bar = 40 |im.

macrophage molecules (Fig. 1.20). Although the two phenomena generally occur together, reactive responses of microglia can be diverse and restricted to subpopulations of cells within a microenvironment. Microglia not only respond to pathological conditions involving immune activation, but also become activated in neurodegenerative conditions that are not considered immune-mediated (Banati and Graeber, 1994). This latter response is indicative of the phago-cytic role of microglia. Microglia change their morphology and antigen expression in response to almost any form of CNS injury.

Summary

Neuroglia are a set of cell types that together subserve supportive and trophic roles critical for the normal functioning of nervous tissue. Certain glial cells—the myelinating cells, for example—have clearly shaped nervous system evolution and development in that they evolved to facilitate rapid conduction of the action potential along small-caliber axons. The coordinated integrative functions of the vertebrate brain therefore depend on a normal complement of myelinated axons. Astrocytes and microglial cells also have major and extremely important functions in development and in tissue injury, but these roles are not yet well understood. In pathological states of all kinds (autoimmune, toxic insult, trauma), these cells react to contain and limit tissue damage. They also contribute in a major way to repair mechanisms.

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