Changes in total cell numbers of the basal ganglia in patients with multiple system atrophy — A stereological study

Salvesen, Lisette; Ullerup, Birgitte H.; Sunay, Fatma Bahar; Brudek, Tomasz; Løkkegaard, Annemette; Agander, Tina Klitmøller; Winge, Kristian; Pakkenberg, Bente

doi:10.1016/j.nbd.2014.11.008

Cited by 68 publications

(106 citation statements)

References 48 publications

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“…The observation of an unchanged or even increased oligodendrocyte density in human MSA post-mortem tissue and MBP29 mice suggests that rather a dysfunction of oligodendrocytes in terms of myelin sheath formation than pronounced loss of oligodendrocytes underlies myelin loss in MSA. A recent stereological analysis, focusing on basal ganglia, has indicated that oligodendrocytes are by far more preserved than neurons in MSA [41]. In line, we and others have observed increased numbers of OPCs in the striatum and the cerebellum of MSA patients, supporting the notion of preserved oligodendrocytic cells in MSA [2, 36].…”

Section: Discussionsupporting

confidence: 87%

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α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

et al. 2016

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Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic α-synuclein on the formation of myelin sheaths in order to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic α-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of α-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel α-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic α-synuclein. Additionally, benztropine restored the α-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the α-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.

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Section: Discussionsupporting

confidence: 87%

“…1a). Oligodendrocytes were identified by morphology in hematoxylin stained sections according to Salvesen and colleagues [41] (Fig. 1a, b).…”

Section: Resultsmentioning

confidence: 99%

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

et al. 2016

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“…GCIs were primarily observed within mature OLGs and were thus suggested to be causal for the widespread myelin loss associated with both axonal and neuronal degeneration in MSA [108, 116]. Notably, the vast myelin loss observed in MSA patients is not accompanied by a severe loss in numbers of mature OLGs [117]. Alterations in the glial compartment within the white matter, however, are not restricted to oligodendroglial cells but include astrocytes and microglia.…”

Section: Oligodendroglial and Myelin Dysfunction In Msamentioning

confidence: 99%

“…Oligodendrocyte progenitor cells (OPCs)System/tissueReference Alpha-synuclein accumulation in OPCsHuman: postmortem[183] Increased numbers of OPCsHuman: postmortem[182, 183]In vivo: MBP model[183] Impaired maturation of alpha-synuclein-expressing OPCsIn vitro: primary and permanent cells[174, 183]B. Oligodendrocytes (OLGs)System/tissueReference GCIsHuman: postmortem[66, 108, 116] Alpha-synuclein as major GCI componentHuman: postmortem[126–128, 152] Modification and insolubility of alpha-synucleinHuman: postmortem[159–163] Correlation between GCIs distribution and neurodegenerationHuman: postmortem[104, 122–125] Moderate loss of OLGsHuman: postmortem[117]In vivo: CNP and PLP models[184, 193, 195] Increased activity of unfolded protein responseHuman: postmortem[157] Altered morphology of oligodendroglial nucleiHuman: postmortem[158] Autophagic and proteasomal dysfunctionIn vitro: primary cells[196] Increased vulnerability toward proteolytic stressIn vivo: PLP model[195] Increased vulnerability toward oxidative stressIn vivo: MBP and PLP models[192, 197, 204–206]In vitro: primary and permanent cells[198–201] Reduced neurotrophic supportIn vivo: MBP model[208, 209]C. MyelinSystem/tissueReference Myelin loss…”

Section: Oligodendroglial and Myelin Dysfunction In Msamentioning

confidence: 99%

“…1a), MSA brains are characterized by a profound myelin and neuronal cell loss accompanied by a severe inflammation such as widespread astrogliosis and microgliosis (Fig. 1d) [117, 211]. Additionally, OPCs contribute to MSA pathology as recent studies demonstrate the presence of alpha-synuclein accumulation within OPCs and increased OPC numbers in MSA patients.…”

Section: Oligodendroglial and Myelin Dysfunction In Msamentioning

confidence: 99%

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Oligodendroglia and Myelin in Neurodegenerative Diseases: More Than Just Bystanders?

2015

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Oligodendrocytes, the myelinating cells of the central nervous system, mediate rapid action potential conduction and provide trophic support for axonal as well as neuronal maintenance. Their progenitor cell population is widely distributed in the adult brain and represents a permanent cellular reservoir for oligodendrocyte replacement and myelin plasticity. The recognition of oligodendrocytes, their progeny, and myelin as contributing factors for the pathogenesis and the progression of neurodegenerative disease has recently evolved shaping our understanding of these disorders. In the present review, we aim to highlight studies on oligodendrocytes and their progenitors in neurodegenerative diseases. We dissect oligodendroglial biology and illustrate evolutionary aspects in regard to their importance for neuronal functionality and maintenance of neuronal circuitries. After covering recent studies on oligodendroglia in different neurodegenerative diseases mainly in view of their function as myelinating cells, we focus on the alpha-synucleinopathy multiple system atrophy, a prototypical disorder with a well-defined oligodendroglial pathology.

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Implication of cerebral astrocytes in major depression: A review of fine neuroanatomical evidence in humans

O’Leary

Mechawar

2021

Glia

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Postmortem investigations have implicated astrocytes in many neurological and psychiatric conditions. Multiple brain regions from individuals with major depressive disorder (MDD) have lower expression levels of astrocyte markers and lower densities of astrocytes labeled for these markers, suggesting a loss of astrocytes in this mental illness. This paper reviews the general properties of human astrocytes, the methods to study them, and the postmortem evidence for astrocyte pathology in MDD. When comparing astrocyte density and morphometry studies, astrocytes are more abundant and smaller in human subcortical than cortical brain regions, and immunohistochemical labeling for the astrocyte markers glial fibrillary acidic protein (GFAP) and vimentin (VIM) reveals fewer than 15% of all astrocytes that are present in cortical and subcortical regions, as revealed using other staining techniques. By combining astrocyte densities and morphometry, a model was made to illustrate that domain organization is mostly limited to GFAP‐IR astrocytes. Using these markers and others, alterations of astrocyte densities appear more widespread than those for astrocyte morphologies throughout the brain of individuals having died with MDD. This review suggests how reduced astrocyte densities may relate to the association of depressive episodes in MDD with elevated S100 beta (S100B) cerebrospinal fluid serum levels. Finally, a potassium imbalance theory is proposed that integrates the reduced astrocyte densities generated from postmortem studies with a hypothesis for the antidepressant effects of ketamine generated from rodent studies.

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Changes in total cell numbers of the basal ganglia in patients with multiple system atrophy — A stereological study

Cited by 68 publications

References 48 publications

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

Oligodendroglia and Myelin in Neurodegenerative Diseases: More Than Just Bystanders?

Implication of cerebral astrocytes in major depression: A review of fine neuroanatomical evidence in humans

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