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Journal ArticleDOI

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

01 Sep 2017-Acta Neuropathologica (Springer Verlag)-Vol. 134, Iss: 3, pp 351-382
TL;DR: A novel classification of leukodystrophies is proposed that takes into account the primary involvement of any white matter component, and Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin; astrocytopathies; leuko-axonopathies; microgliopathy; andLeuko-vasculopathies.
Abstract: 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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Citations
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Journal ArticleDOI
TL;DR: The biology of myelin, the expanded relationship of myelinating oligodendrocytes with its underlying axons and the neighboring cells, and its disturbances in various diseases such as multiple sclerosis, acute disseminated encephalomyelitis, and neuromyELitis optica spectrum disorders are reviewed.
Abstract: Oligodendrocytes generate multiple layers of myelin membrane around axons of the central nervous system to enable fast and efficient nerve conduction. Until recently, saltatory nerve conduction was...

274 citations

Journal ArticleDOI
TL;DR: The results suggest that CSF1R is required for human brain development and establish the csf1rDM fish as a model for microgliopathies and exemplify an under-recognized form of phenotypic expansion.
Abstract: Microglia are CNS-resident macrophages that scavenge debris and regulate immune responses. Proliferation and development of macrophages, including microglia, requires Colony Stimulating Factor 1 Receptor (CSF1R), a gene previously associated with a dominant adult-onset neurological condition (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). Here, we report two unrelated individuals with homozygous CSF1R mutations whose presentation was distinct from ALSP. Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia. The second individual had a homozygous missense mutation (c.1929C>A [p.His643Gln]) and presented with developmental delay and epilepsy in childhood. We analyzed a zebrafish model (csf1rDM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor. CUX1+ neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1+ neurons. Since a large fraction of CUX1+ neurons project callosal axons, we speculate that microglia deficiency may contribute to agenesis of the corpus callosum via reduction in CUX1+ neurons. Our results suggest that CSF1R is required for human brain development and establish the csf1rDM fish as a model for microgliopathies. In addition, our results exemplify an under-recognized form of phenotypic expansion, in which genes associated with well-recognized, dominant conditions produce different phenotypes when biallelically mutated.

141 citations

Journal ArticleDOI
TL;DR: It is demonstrated that WM degeneration encompasses multiple substrates and therefore more than one pharmacological approach is necessary to preserve axonal function and prevent cognitive impairment.
Abstract: Advances in neuroimaging have enabled greater understanding of the progression of cerebral degenerative processes associated with ageing-related dementias. Leukoaraiosis or rarefied white matter (WM) originally described on computed tomography is one of the most prominent changes which occurs in older age. White matter hyperintensities (WMH) evident on magnetic resonance imaging have become commonplace to describe WM changes in relation to cognitive dysfunction, types of stroke injury, cerebral small vessel disease and neurodegenerative disorders including Alzheimer's disease. Substrates of WM degeneration collectively include myelin loss, axonal abnormalities, arteriolosclerosis and parenchymal changes resulting from lacunar infarcts, microinfarcts, microbleeds and perivascular spacing. WM cells incorporating astrocytes, oligodendrocytes, pericytes and microglia are recognized as key cellular components of the gliovascular unit. They respond to ongoing pathological processes in different ways leading to disruption of the gliovascular unit. The most robust alterations involve oligodendrocyte loss and astrocytic clasmatodendrosis with displacement of the water channel protein, aquaporin 4. These modifications likely precede arteriolosclerosis and capillary degeneration and involve tissue oedema, breach of the blood-brain barrier and induction of a chronic hypoxic state in the deep WM. Several pathophysiological mechanisms are proposed to explain how WM changes commencing with haemodynamic changes within the vascular system impact on cognitive dysfunction. Animal models simulating cerebral hypoperfusion in man have paved the way for several translational opportunities. Various compounds with variable efficacies have been tested to reduce oxidative stress, inflammation and blood-brain barrier damage in the WM. Our review demonstrates that WM degeneration encompasses multiple substrates and therefore more than one pharmacological approach is necessary to preserve axonal function and prevent cognitive impairment. This article is part of the Special Issue "Vascular Dementia".

139 citations

Journal ArticleDOI
TL;DR: The current knowledge of CSF1R-related leukoencephalopathy is addressed and the putative pathophysiology is discussed, with a focus on microglia, as well as future research directions.
Abstract: Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s–50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with CSF1R mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which CSF1R mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of CSF1R-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions.

101 citations


Cites background from "Leukodystrophies: a proposed classi..."

  • ...Moreover, it has attracted attention in terms of primary microgliopathy.(5,7) Clinical, radiologic, and pathologic characteristics have since been elucidated; however, there are still many questions to be answered....

    [...]

Journal ArticleDOI
03 Mar 2020-Cells
TL;DR: Emerging evidence of astrocyte-oligodendrocytes communication in health and disease is reviewed to reveal important insights into the pathogenesis and treatment of CNS diseases.
Abstract: Over the last decade knowledge of the role of astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive role in response to damage it is clear that astrocytes actively maintain CNS homeostasis by influencing pH, ion and water balance, the plasticity of neurotransmitters and synapses, cerebral blood flow, and are important immune cells. During disease astrocytes become reactive and hypertrophic, a response that was long considered to be pathogenic. However, recent studies reveal that astrocytes also have a strong tissue regenerative role. Whilst most astrocyte research focuses on modulating neuronal function and synaptic transmission little is known about the cross-talk between astrocytes and oligodendrocytes, the myelinating cells of the CNS. This communication occurs via direct cell-cell contact as well as via secreted cytokines, chemokines, exosomes, and signalling molecules. Additionally, this cross-talk is important for glial development, triggering disease onset and progression, as well as stimulating regeneration and repair. Its critical role in homeostasis is most evident when this communication fails. Here, we review emerging evidence of astrocyte-oligodendrocyte communication in health and disease. Understanding the pathways involved in this cross-talk will reveal important insights into the pathogenesis and treatment of CNS diseases.

95 citations

References
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Journal ArticleDOI
TL;DR: Astrocyte functions in healthy CNS, mechanisms and functions of reactive astrogliosis and glial scar formation, and ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions are reviewed.
Abstract: Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

4,075 citations


"Leukodystrophies: a proposed classi..." refers background in this paper

  • ...They are an extremely heterogeneous cell type essential for brain development and maintenance of CNS homeostasis [205]....

    [...]

  • ...Astrocytes induce and preserve the integrity of the blood–brain and blood–cerebrospinal fluid barriers, control the extracellular ionic milieu, provide metabolic support to neurons, facilitate perivascular flow of cerebrospinal fluid, ensure proper synaptic transmission and plasticity, and are involved in cerebral blood flow regulation [11, 96, 205]....

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Journal ArticleDOI
TL;DR: This review focuses on several key observations that illustrate the multi-faceted activities of microglia in the normal and pathologic brain.
Abstract: Microglial cells constitute the resident macrophage population of the CNS. Recent in vivo studies have shown that microglia carry out active tissue scanning, which challenges the traditional notion of 'resting' microglia in the normal brain. Transformation of microglia to reactive states in response to pathology has been known for decades as microglial activation, but seems to be more diverse and dynamic than ever anticipated—in both transcriptional and nontranscriptional features and functional consequences. This may help to explain why engagement of microglia can be either neuroprotective or neurotoxic, resulting in containment or aggravation of disease progression. Moreover, little is known about the heterogeneity of microglial responses in different pathologic contexts that results from regional adaptations or from the progression of a disease. In this review, we focus on several key observations that illustrate the multi-faceted activities of microglia in the normal and pathologic brain.

3,238 citations


"Leukodystrophies: a proposed classi..." refers background in this paper

  • ...Being the major immune effectors of the CNS, they also act as surveillance cells and sensors of pathologic events [85]....

    [...]

Journal ArticleDOI
15 Nov 1984-Nature
TL;DR: It is reported here that microtubules in vitro coexist in growing and shrinking populations which interconvert rather infrequently and this dynamic instability is a general property of micro Tubules and may be fundamental in explaining cellular microtubule organization.
Abstract: We report here that microtubules in vitro coexist in growing and shrinking populations which interconvert rather infrequently. This dynamic instability is a general property of microtubules and may be fundamental in explaining cellular microtubule organization.

3,108 citations


"Leukodystrophies: a proposed classi..." refers background in this paper

  • ...An essential feature is their dynamic instability that is the possibility to rapidly de- and repolymerize in response to the environment [143]....

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Journal ArticleDOI
TL;DR: Small vessel disease has an important role in cerebrovascular disease and is a leading cause of cognitive decline and functional loss in the elderly and should be a main target for preventive and treatment strategies, but all types of presentation and complications should be taken into account.
Abstract: Summary The term cerebral small vessel disease refers to a group of pathological processes with various aetiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. Age-related and hypertension-related small vessel diseases and cerebral amyloid angiopathy are the most common forms. The consequences of small vessel disease on the brain parenchyma are mainly lesions located in the subcortical structures such as lacunar infarcts, white matter lesions, large haemorrhages, and microbleeds. Because lacunar infarcts and white matter lesions are easily detected by neuroimaging, whereas small vessels are not, the term small vessel disease is frequently used to describe the parenchyma lesions rather than the underlying small vessel alterations. This classification, however, restricts the definition of small vessel disease to ischaemic lesions and might be misleading. Small vessel disease has an important role in cerebrovascular disease and is a leading cause of cognitive decline and functional loss in the elderly. Small vessel disease should be a main target for preventive and treatment strategies, but all types of presentation and complications should be taken into account.

2,330 citations


"Leukodystrophies: a proposed classi..." refers background in this paper

  • ...Cerebral AD arteriopathy with subcortical infarcts and leukoencephalopathy [162]...

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  • ...Cerebral AR arteriopathy with subcortical infarcts and leukoencephalopathy [162]...

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Book
01 Jan 2000
TL;DR: Origins and Principles of Translational Control, Genetic Approaches to Translation Initiation in Saccharomyces cerevisiae, and Programmed translational Frameshifting, Hopping, an
Abstract: Origins and Principles of Translational Control (M.B. Mathews, N. Sonenberg, and J.W.B. Hershey) Pathway and Mechanism of Initiation of Protein Synthesis (J.W.B. Hershey and W.C. Merrick) Protein Bioynthesis Elongation Cycle (W.C. Merrick and J. Nyborg) Comparative View of Initiation Site Selection Mechanisms (R.J. Jackson) Mechanism and Regulation of Initiator Methionyl-tRNA Binding to Ribosomes (A.G. Hinnebusch) Regulation of Ribosomal Recruitment in Eukaryotes (B. Raught, A.-C. Gingras, and N. Sonenberg) Translational Control of Developmental Decisions (M. Wickens, E.B. Goodwin, J. Kimble, S. Strickland, and M. Hentze) Viral Translational Strategies and Host Defense Mechanisms (T. Pe'ery and M.B. Mathews) Ribosomal Subunit Joining (T.V. Pestova, T.E. Dever, and C.U.T. Hellen) Physical and Functional Interactions between the mRNA Cap Structure and the Poly(A) Tail (A. Sachs) Translation Termination: It's Not the End of the Story (E.M. Welch, W. Wang, and S.W. Peltz) Genetic Approaches to Translation Initiation in Saccharomyces cerevisiae (T.F. Donahue) Double-stranded RNA-activated Protein Kinase PKR (R.J. Kaufman) Heme-regulated eIF2 alpha Kinase (J.-J. Chen) PERK and Translational Control by Stress in the Endoplasmic Reticulum (D. Ron and H.P. Harding) Regulation of Translation Initiation in Mammalian Cells by Amino Acids (S.R. Kimball and L.S. Jefferson) Translational Control during Heat Shock (R.J. Schneider) Translational Control by Upstream Open Reading Frames (A.P. Geballe and M.S. Sachs) Cellular Internal Ribosome Entry Site Elements and the Use of cDNA Microarrays in Their Investigation (M.S. Carter, K.M. Kuhn, and P. Sarnow) Translational Control and Cancer (J.W.B. Hershey and S. Miyamoto) Translational Control of Ferritin Synthesis (T.A. Rouault and J.B. Harford) Translational Control of TOP mRNAs (O. Meyuhas and E. Hornstein) S6 Phosphorylation and Signal Transduction (S. Fumagalli and G. Thomas) Control of the Elongation Phase of Protein Synthesis (C. Proud) Programmed Translational Frameshifting, Hopping, an

1,422 citations

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