Abstract:The authors show that central nervous system myelin lacking proteolipid protein (PLP) induces mitochondrial dysfunction, including altered motility, degeneration, and ectopic smooth endoplasmic reticulum interactions, leading to axonal structural defects and degeneration. Mutated PLP occurs in hereditary spastic paraplegia, and these cellular effects provide potential insight into the pathology of the disease.
“…It is conceivable that they cause local damage of the juxtaparanodal aspects of oligodendrocytes. Similar changes in axonal transport and juxtaparanodal regions have been recently reported for a mutant of unknown disease relevance in which PLP is replaced by the peripheral nerve myelin protein P0 (Yin et al, 2016). Alternatively, the T-lymphocytes may have a direct detrimental impact on the axons, possibly via the nearby nodes of Ranvier, where the axon is exposed.…”
Section: Pelizaeus-merzbacher Disease a N D Sp A S T I C P A R A P supporting
Genetically caused neurological disorders of the central nervous system (CNS) are usually orphan diseases with poor or even fatal clinical outcome and few or no treatments that will improve longevity or at least quality of life. Neuroinflammation is common to many of these disorders, despite the fact that a plethora of distinct mutations and molecular changes underlie the disorders. In this article, data from corresponding animal models are analyzed to define the roles of innate and adaptive inflammation as modifiers and amplifiers of disease. We describe both common and distinct patterns of neuroinflammation in genetically mediated CNS disorders and discuss the contrasting mechanisms that lead to adverse versus neuroprotective effects. Moreover, we identify the juxtaparanode as a neuroanatomical compartment commonly associated with inflammatory cells and ongoing axonopathic changes, in models of diverse diseases. The identification of key immunological effector pathways that amplify neuropathic features should lead to realistic possibilities for translatable therapeutic interventions using existing immunomodulators. Moreover, evidence emerges that neuroinflammation is not only able to modify primary neural damage-related symptoms but also may lead to unexpected clinical outcomes such as neuropsychiatric syndromes.
“…It is conceivable that they cause local damage of the juxtaparanodal aspects of oligodendrocytes. Similar changes in axonal transport and juxtaparanodal regions have been recently reported for a mutant of unknown disease relevance in which PLP is replaced by the peripheral nerve myelin protein P0 (Yin et al, 2016). Alternatively, the T-lymphocytes may have a direct detrimental impact on the axons, possibly via the nearby nodes of Ranvier, where the axon is exposed.…”
Section: Pelizaeus-merzbacher Disease a N D Sp A S T I C P A R A P supporting
Genetically caused neurological disorders of the central nervous system (CNS) are usually orphan diseases with poor or even fatal clinical outcome and few or no treatments that will improve longevity or at least quality of life. Neuroinflammation is common to many of these disorders, despite the fact that a plethora of distinct mutations and molecular changes underlie the disorders. In this article, data from corresponding animal models are analyzed to define the roles of innate and adaptive inflammation as modifiers and amplifiers of disease. We describe both common and distinct patterns of neuroinflammation in genetically mediated CNS disorders and discuss the contrasting mechanisms that lead to adverse versus neuroprotective effects. Moreover, we identify the juxtaparanode as a neuroanatomical compartment commonly associated with inflammatory cells and ongoing axonopathic changes, in models of diverse diseases. The identification of key immunological effector pathways that amplify neuropathic features should lead to realistic possibilities for translatable therapeutic interventions using existing immunomodulators. Moreover, evidence emerges that neuroinflammation is not only able to modify primary neural damage-related symptoms but also may lead to unexpected clinical outcomes such as neuropsychiatric syndromes.
“…It is likely that the presence of cytosolic channels affects the intracellular transport routes between oligodendroglial cell body and the inner tongue of myelin and thus the transport of small metabolites that are exchanged between oligodendrocytes and axons, thereby providing trophic support (Frühbeis et al, ; Fünfschilling et al, ; Lee et al, ; Nave, ; Nave & Werner, ; Snaidero et al, ). Indeed, impaired trophic support by oligodendrocytes may cause the pathology of myelinated axons, including reduced ATP levels (Trevisiol et al, ), impaired fast retrograde and anterograde transport and mitochondria (Edgar, McLaughlin, Yool, et al, ; Yin et al, ) and ultimately axonal spheroids and degeneration (Garbern et al, ; Griffiths et al, ; Gruenenfelder et al, ).…”
Proteolipid protein (PLP) is the most abundant integral membrane protein in compact central nervous system myelin, and null mutations of the PLP1 gene cause spastic paraplegia type 2 (SPG2). SPG2 patients and PLP-deficient mice exhibit only moderate abnormalities of myelin but progressive degeneration of long axons. Since Plp1 gene products are detected in a subset of neurons it has been suggested that the loss of neuronal Plp1 expression could be the cause of the axonal pathology. To test this hypothesis, we created mice with a floxed Plp1 allele for selective Cre-mediated recombination in neurons. We find that recombination of Plp1 in excitatory projection neurons does not cause neuropathology, whereas oligodendroglial targeting of Plp1 is sufficient to cause the entire neurodegenerative spectrum of SPG2 including axonopathy and secondary neuroinflammation. We conclude that PLP-dependent loss of oligodendroglial support is the primary cause of axonal degeneration in SPG2.
“…It is possible that lactate deprivation through knockdown of oligodendrocyte MCT1 may cause cellular dysfunction through unknown mechanisms. We have previously discussed how dysfunctional oligodendrocytes can induce axonal degeneration, even when myelin sheaths remain intact (Edgar et al, ; Griffiths et al, ; Lappe‐Siefke et al, ; Yin et al, ). Overall, additional experiments in which oligodendrocyte‐derived lactate is directly labeled and traced are needed in order to prove the proposed model.How is oligodendrocyte metabolism altered during development and in response to neuronal activity?How do oxphos and glycolysis contribute to energy production in myelinated axons during rest and neuronal activation?Is oligodendrocyte‐derived lactate exported to axons and metabolized for energy production?…”
Section: Energetic Coupling Of Glia and Axonsmentioning
The unique polarization and high‐energy demand of neurons necessitates specialized mechanisms to maintain energy homeostasis throughout the cell, particularly in the distal axon. Mitochondria play a key role in meeting axonal energy demand by generating adenosine triphosphate through oxidative phosphorylation. Recent evidence demonstrates how axonal mitochondrial trafficking and anchoring are coordinated to sense and respond to altered energy requirements. If and when these mechanisms are impacted in pathological conditions, such as injury and neurodegenerative disease, is an emerging research frontier. Recent evidence also suggests that axonal energy demand may be supplemented by local glial cells, including astrocytes and oligodendrocytes. In this review, we provide an updated discussion of how oxidative phosphorylation, aerobic glycolysis, and oligodendrocyte‐derived metabolic support contribute to the maintenance of axonal energy homeostasis.
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