Julia M. Edgar

Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity.

Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon–glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon–glia metabolic coupling serves a physiological function.

Axonal Transport Defects in Neurodegenerative Diseases

Adult-onset neurodegenerative diseases (AONDs) comprise a heterogeneous group of neurological disorders characterized by a progressive, age-dependent decline in neuronal function and loss of selected neuronal populations. Alterations in synaptic function and axonal connectivity represent early and critical pathogenic events in AONDs, but molecular mechanisms underlying these defects remain elusive. The large size and complex subcellular architecture of neurons render them uniquely vulnerable to alterations in axonal transport (AT). Accordingly, deficits in AT have been documented in most AONDs, suggesting a common defect acquired through different pathogenic pathways. These observations suggest that many AONDs can be categorized as dysferopathies, diseases in which alterations in AT represent a critical component in pathogenesis. Topics here address various molecular mechanisms underlying alterations in AT in several AONDs. Illumination of such mechanisms provides a framework for the development of novel therapeutic strategies aimed to prevent axonal and synaptic dysfunction in several major AONDs.

Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia.

Oligodendrocytes are critical for the development of the plasma membrane and cytoskeleton of the axon. In this paper, we show that fast axonal transport is also dependent on the oligodendrocyte. Using a mouse model of hereditary spastic paraplegia type 2 due to a null mutation of the myelin Plp gene, we find a progressive impairment in fast retrograde and anterograde transport. Increased levels of retrograde motor protein subunits are associated with accumulation of membranous organelles distal to nodal complexes. Using cell transplantation, we show categorically that the axonal phenotype is related to the presence of the overlying Plp null myelin. Our data demonstrate a novel role for oligodendrocytes in the local regulation of axonal function and have implications for the axonal loss associated with secondary progressive multiple sclerosis.

Myelin Membrane Wrapping of CNS Axons by PI(3,4,5)P3-Dependent Polarized Growth at the Inner Tongue

Central nervous system myelin is a multilayered membrane sheath generated by oligodendrocytes for rapid impulse propagation. However, the underlying mechanisms of myelin wrapping have remained unclear. Using an integrative approach of live imaging, electron microscopy, and genetics, we show that new myelin membranes are incorporated adjacent to the axon at the innermost tongue. Simultaneously, newly formed layers extend laterally, ultimately leading to the formation of a set of closely apposed paranodal loops. An elaborated system of cytoplasmic channels within the growing myelin sheath enables membrane trafficking to the leading edge. Most of these channels close with ongoing development but can be reopened in adults by experimentally raising phosphatidylinositol-(3,4,5)-triphosphate levels, which reinitiates myelin growth. Our model can explain assembly of myelin as a multilayered structure, abnormal myelin outfoldings in neurological disease, and plasticity of myelin biogenesis observed in adult life.

Neuroprotection and repair in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease that is considered by many people to have an autoimmune aetiology. In recent years, new data emerging from histopathology, imaging and other studies have expanded our understanding of the disease and may change the way in which it is treated. Conceptual shifts have included: first, an appreciation of the extent to which the neuron and its axon are affected in MS, and second, elucidation of how the neurobiology of axon–glial and, particularly, axon–myelin interaction may influence disease progression. In this article, we review advances in both areas, focusing on the molecular mechanisms underlying axonal loss in acute inflammation and in chronic demyelination, and discussing how the restoration of myelin sheaths via the regenerative process of remyelination might prevent axon degeneration. An understanding of these processes could lead to better strategies for the prevention and treatment of axonal loss, which will ultimately benefit patients with MS.

Early ultrastructural defects of axons and axon–glia junctions in mice lacking expression of Cnp1

Most axons in the central nervous system (CNS) are surrounded by a multilayered myelin sheath that promotes fast, saltatory conduction of electrical impulses. By insulating the axon, myelin also shields the axoplasm from the extracellular milieu. In the CNS, oligodendrocytes provide support for the long‐term maintenance of myelinated axons, independent of the myelin sheath. Here, we use electron microscopy and morphometric analyses to examine the evolution of axonal and oligodendroglial changes in mice deficient in 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase (CNP) and in mice deficient in both CNP and proteolipid protein (PLP/DM20). We show that CNP is necessary for the formation of a normal inner tongue process of oligodendrocytes that myelinate small diameter axons. We also show that axonal degeneration in Cnp1 null mice is present very early in postnatal life. Importantly, compact myelin formed by transplanted Cnp1 null oligodendrocytes induces the same degenerative changes in shiverer axons that normally are dysmyelinated but structurally intact. Mice deficient in both CNP and PLP develop a more severe axonal phenotype than either single mutant, indicating that the two oligodendroglial proteins serve distinct functions in supporting the myelinated axon. These observations support a model in which the trophic functions of oligodendrocytes serve to offset the physical shielding of axons by myelin membranes.

Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the Shiverer mouse

Axonal pathology in multiple sclerosis (MS) has been described for over a century, but new insights into axonal loss and disability have refocused interest in this area. There is evidence of oxidative damage to mitochondrial DNA in chronic MS plaques, suggesting that mitochondrial failure may play a role in MS pathology. We propose that in the chronic absence of myelin the maintenance of conduction relies partially on an increase in mitochondria to provide energy. This increased energy requirement also promotes reactive oxygen species (ROS), because most intraaxonal ROS are generated by mitochondria. If antioxidant defenses are overwhelmed by an excess of ROS, this may result in damage to the axon. Our aim was to investigate whether a chronic lack of myelin results in adaptive changes involving mitochondria within the axon. We investigated this in the shiverer mouse. This myelin basic protein gene mutant provides a model of how adult central nervous system (CNS) axons cope with the chronic absence of a compact myelin sheath. Cytochrome c histochemistry demonstrated a twofold increase in mitochondrial activity in white matter tracts of shiverer, and electron microscopy confirmed a significantly higher number of mitochondria within the dysmyelinated axons. Our data demonstrate that there are adaptive changes involving mitochondria occurring within CNS axons in shiverer mice in response to a lack of myelin. This work contributes to our understanding of the adaptive changes occurring in response to a lack of myelin in a noninflammatory environment similar to the situation seen in chronically demyelinated MS plaques.

The myelinated axon is dependent on the myelinating cell for support and maintenance: Molecules involved

The myelin‐forming cells, oligodendrocytes and Schwann cells, extend processes that spirally wrap axons and provide the insulation that allows rapid saltatory conduction. Recent data suggest a further role for the myelin‐forming cells in axonal support and maintenance. This Mini‐Review summarises some of the data that support this view and highlights the molecules involved.

PLP overexpression perturbs myelin protein composition and myelination in a mouse model of Pelizaeus-Merzbacher disease

Duplication of PLP1, an X‐linked gene encoding the major myelin membrane protein of the human CNS, is the most frequent cause of Pelizaeus‐Merzbacher disease (PMD). Transgenic mice with extra copies of the wild type Plp1 gene, a valid model of PMD, also develop a dysmyelinating phenotype dependant on gene dosage. In this study we have examined the effect of increasing Plp1 gene dosage on levels of PLP/DM20 and on other representative myelin proteins. In cultured oligodendrocytes and early myelinating oligodendrocytes in vivo, increased gene dosage leads to elevated levels of PLP/DM20 in the cell body. During myelination, small increases in Plp1 gene dosage (mice hemizygous for the transgene) elevate the level of PLP/DM20 in oligodendrocyte soma but cause only minimal and transient effects on the protein composition and structure of myelin suggesting that cells can regulate the incorporation of proteins into myelin. However, larger increases in dosage (mice homozygous for the transgene) are not well tolerated, leading to hypomyelination and alteration in the cellular distribution of PLP/DM20. A disproportionate amount of PLP/DM20 is retained in the cell soma, probably in autophagic vacuoles and lysosomes whereas the level in myelin is reduced. Increased Plp1 gene dosage affects other myelin proteins, particularly MBP, which is transitorily reduced in hemizygous mice but consistently and markedly lower in homozygotes in both myelin and naïve or early myelinating oligodendrocytes. Whether the reduced MBP is implicated in the pathogenesis of dysmyelination is yet to be established.

Demyelination and axonal preservation in a transgenic mouse model of Pelizaeus-Merzbacher disease

It is widely thought that demyelination contributes to the degeneration of axons and, in combination with acute inflammatory injury, is responsible for progressive axonal loss and persistent clinical disability in inflammatory demyelinating disease. In this study we sought to characterize the relationship between demyelination, inflammation and axonal transport changes using a Plp1‐transgenic mouse model of Pelizaeus‐Merzbacher disease. In the optic pathway of this non‐immune mediated model of demyelination, myelin loss progresses from the optic nerve head towards the brain, over a period of months. Axonal transport is functionally perturbed at sites associated with local inflammation and ‘damaged’ myelin. Surprisingly, where demyelination is complete, naked axons appear well preserved despite a significant reduction of axonal transport. Our results suggest that neuroinflammation and/or oligodendrocyte dysfunction are more deleterious for axonal health than demyelination per se, at least in the short term.