<scp>P</scp>elizaeus–<scp>M</scp>erzbacher disease: Cellular pathogenesis and pharmacologic therapy

Torii, Tomohiro; Miyamoto, Yuki; Yamauchi, Junji; Tanoue, Akito

doi:10.1111/ped.12450

Cited by 43 publications

(44 citation statements)

References 76 publications

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“…We also recognize the importance of performing a study that examines inflammation in PMD autopsy tissue. Describing the central pathologic differences between PLP1 mutation types in humans is worthy of attention because it should lead to a more refined discussion on future therapies [55]. For example, in the PLP1 deletion patient, extensive myelin, albeit of abnormal composition, is present and is likely indicative of numerous functional oligodendrocytes.…”

Section: Resultsmentioning

confidence: 99%

“…More than 100 point mutations have been identified within the PLP1 coding region that cause a wide spectrum of clinical abnormalities. The clinical features of PMD describing the aggressiveness of the disease and how the severity depends on the nature of the PLP1 mutation and gene expression has been well studied in animal models [22, 26, 35, 51, 55, 64, 67]. …”

Section: Introductionmentioning

confidence: 99%

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Novel pathologic findings in patients with Pelizaeus-Merzbacher disease

Laukka

Kamholz

Bessert

et al. 2016

Neuroscience Letters

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Pelizaeus-Merzbacher disease (PMD) is an X-linked inherited hypomyelinating disorder caused by mutations in the gene encoding proteolipid protein (PLP), the major structural protein in central nervous system (CNS) myelin. Prior to our study, whether hypomyelination in PMD was caused by demyelination, abnormally thin sheaths or failure to form myelin was unknown. In this study, we compared the microscopic pathology of myelin from brain tissue of 3 PMD patients with PLP1 duplications to that of a patient with a complete PLP1 deletion. Autopsy tissue procured from PMD patients was embedded in paraffin for immunocytochemistry and plastic for electron microscopy to obtain highresolution fiber pathology of cerebrum and corpus callosum. Through histological stains, immunocytochemistry and electron microscopy, our study illustrates unique pathologic findings between the two different types of mutations. Characteristic of the patient with a PLP1 deletion, myelin sheaths showed splitting and decompaction of myelin, confirming for the first time that myelin in PLP1 deletion patients is similar to that of rodent models with gene deletions. Myelin thickness and g-ratios of some fibers, in relation to axon diameter was abnormally thin, suggesting that oligodendrocytes remain metabolically functional and/or are attempting to make myelin. Many fibers showed swollen, progressive degenerative changes to axons in addition to the dissolution of myelin. All three duplication cases shared remarkable fiber pathology including swellings, constriction and/or transection and involution of myelin. Characteristic of PLP1 duplication patients, many axons showed segmental demyelination along their length. Still other axons had abnormally thick myelin sheaths, suggestive of continued myelination. Thus, each type of mutation exhibited unique pathology even though commonality to both mutations included involution of myelin, myelin balls and degeneration of axons. This pathology study describes findings unique to each mutation that suggests the mechanism causing fiber pathology is likewise heterogeneous.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel pathologic findings in patients with Pelizaeus-Merzbacher disease

Laukka

Kamholz

Bessert

et al. 2016

Neuroscience Letters

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“…PLP1 point mutations and duplications confer a toxic gain of function in oligodendrocytes, with consequent misfolding and aggregation of mutated PLP1 [ 46 ]. Under normal conditions, PLP1 is synthesized at the endoplasmic reticulum (ER)/Golgi apparatus, associates with lipids and is transported to myelin by vesicular transport [ 224 ]. PLP1 point mutations prevent normal trafficking of the PLP1 protein to the cytoplasmic membrane and cause its aggregation in the ER and Golgi apparatus with activation of the unfolded protein response.…”

Section: Pathology and Mechanisms Of Genetic White Matter Disorders: mentioning

confidence: 99%

Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

2017

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Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies.

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“…We have reported that changes of protein properties caused by their disease mutations are associated with their disease phenotypes of oligodendrocytes [3], [4], [5], [6], [7]. We herein report that transgenic mice expressing HLD4-associated (Asp-29-to-Gly) mutant of HSPD1 exhibit a defect in myelination in brain.…”

mentioning

confidence: 71%

Pelizaeus–Merzbacher disease: Cellular pathogenesis and pharmacologic therapy

Cited by 43 publications

References 76 publications

Novel pathologic findings in patients with Pelizaeus-Merzbacher disease

Novel pathologic findings in patients with Pelizaeus-Merzbacher disease

Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

Defective myelination in mice harboring hypomyelinating leukodystrophy-associated HSPD1 mutation

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