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

Ettle, Benjamin; Kerman, Bilal E.; Valera, Elvira; Gillmann, Clarissa; Schlachetzki, J; Reiprich, Simone; Büttner, Christian; Ekici, Arif B.; Reis, André; Wegner, Michael; Bäuerle, Tobias; Riemenschneider, Markus J.; Masliah, Eliezer; Gage, Fred H.

doi:10.1007/s00401-016-1572-y

Cited by 63 publications

(82 citation statements)

References 55 publications

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“…Library preparation and sequencing of primary OPCs transduced with EF1α‐hu‐α‐syn‐IRES‐GFP (n = 4) or EF1α‐IRES‐GFP lentiviral vectors (n = 3) was performed as described previously . Briefly, RNA quality was determined and a corresponding library was prepared.…”

Section: Methodsmentioning

confidence: 99%

Oligodendroglial α‐synucleinopathy‐driven neuroinflammation in multiple system atrophy

et al. 2019

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Neuroinflammation and oligodendroglial cytoplasmic α‐synuclein (α‐syn) inclusions (GCIs) are important neuropathological characteristics of multiple system atrophy (MSA). GCIs are known to interfere with oligodendroglial maturation and consequently result in myelin loss. The neuroinflammatory phenotype in the context of MSA, however, remains poorly understood. Here, we demonstrate MSA‐associated neuroinflammation being restricted to myeloid cells and tightly linked to oligodendroglial α‐syncleinopathy. In human putaminal post‐mortem tissue of MSA patients, neuroinflammation was observed in white matter regions only. This locally restricted neuroinflammation coincided with elevated numbers of α‐syn inclusions, while gray matter with less α‐synucleinopathy remained unaffected. In order to analyze the temporal pattern of neuroinflammation, a transgenic mouse model overexpressing human α‐syn under the control of an oligodendrocyte‐specific myelin basic protein (MBP) promoter (MBP29‐hα‐syn mice) was assessed in a pre‐symptomatic and symptomatic disease stage. Strikingly, we detected an increased neuroinflammation in regions with a high α‐syn load, the corpus callosum and the striatum, of MBP29‐hα‐syn mice, already at a pre‐symptomatic stage. Furthermore, this inflammatory response was restricted to myeloid cells being highly proliferative and showing an activated, phagocytic phenotype. In contrast, severe astrogliosis was observed only in gray matter regions of MSA patients as well as MBP29‐hα‐syn mice. To further characterize the influence of oligodendrocytes on initiation of the myeloid immune response, we performed RNA sequencing analysis of α‐syn overexpressing primary oligodendrocytes. A distinct gene expression profile including upregulation of cytokines important for myeloid cell attraction and proliferation was detected in α‐syn overexpressing oligodendrocytes. Additionally, microdissected tissue of MBP29‐hα‐syn mice exhibited a similar cellular gene expression profile in white matter regions even pre‐symptomatically. Collectively, these results imply an early crosstalk between neuroinflammation and oligodendrocytes containing α‐syn inclusions leading to an immune response locally restricted to white matter regions in MSA.

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Section: Methodsmentioning

confidence: 99%

Oligodendroglial α‐synucleinopathy‐driven neuroinflammation in multiple system atrophy

et al. 2019

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“…Myelin abnormalities and loss are a characteristic of MSA [18, 68]. Loss of structural myelin proteins, resulting in affected myelin stability, was suggested to play a causative role in the pathogenesis of MSA [61].…”

Section: Introductionmentioning

confidence: 99%

Higher levels of myelin phospholipids in brains of neuronal α-Synuclein transgenic mice precede myelin loss

Grigoletto¹,

Pukaß

Gamliel

et al. 2017

acta neuropathol commun

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α-Synuclein is a protein involved in the pathogenesis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We investigated the role of neuronal α-Syn in myelin composition and abnormalities. The phospholipid content of purified myelin was determined by 31P NMR in two mouse lines modeling PD, PrP-A53T α-Syn and Thy-1 wt-α-Syn. Significantly higher levels of phospholipids were detected in myelin purified from brains of these α-Syn transgenic mouse models than in control mice. Nevertheless, myelin ultrastructure appeared intact. To further investigate the effect of α-Syn on myelin abnormalities, we systematically analyzed the striatum, a brain region associated with neurodegeneration in PD. An age and disease-dependent loss of myelin basic protein (MBP) signal was detected by immunohistochemistry in striatal striosomes (patches). The age-dependent loss of MBP signal was associated with lower P25α levels in oligodendrocytes. In addition, we found that α-Syn inhibited oligodendrocyte maturation and the formation of membranous sheets in vitro. Based on these results we concluded that neuronal α-Syn is involved in the regulation and/or maintenance of myelin phospholipid. However, axonal hypomyelination in the PD models is evident only in progressive stages of the disease and associated with α-Syn toxicity.

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“…CEM performed operations on fluorescence images and was implemented mainly on the ImageJ platform [17] to be available to a wide range of users. It was able to identify and quantify myelin from large data sets and to detect changes in myelin formation [3], [18]. The algorithm for identification of myelin formation was based on detection of co-localization between neurons and oligodendrocytes.…”

Section: Methodsmentioning

confidence: 99%

DeepMQ: A Deep Learning Approach Based Myelin Quantification in Microscopic Fluorescence Images

Cimen¹,

Çapar

Ekinci

et al. 2018

Preprint

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Oligodendrocytes wrap around the axons and form the myelin. Myelin facilitates rapid neural signal transmission. Any damage to myelin disrupts neuronal communication leading to neurological diseases such as multiple sclerosis (MS). There is no cure for MS. This is, in part, due to lack of an efficient method for myelin quantification during drug screening. In this study, an image analysis based myelin sheath detection method, DeepMQ, is developed. The method consists of a feature extraction step followed by a deep learning based binary classification module. The images, which were acquired on a confocal microscope contain three channels and multiple z-sections. Each channel represents either oligodendroyctes, neurons, or nuclei. During feature extraction, 26-neighbours of each voxel is mapped onto a 2D feature image. This image is, then, fed to the deep learning classifier, in order to detect myelin. Results indicate that 93.38% accuracy is achieved in a set of fluorescence microscope images of mouse stem cell-derived oligodendroyctes and neurons. To the best of authors' knowledge, this is the first study utilizing image analysis along with machine learning techniques to quantify myelination.

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

Cited by 63 publications

References 55 publications

Oligodendroglial α‐synucleinopathy‐driven neuroinflammation in multiple system atrophy

Oligodendroglial α‐synucleinopathy‐driven neuroinflammation in multiple system atrophy

Higher levels of myelin phospholipids in brains of neuronal α-Synuclein transgenic mice precede myelin loss

DeepMQ: A Deep Learning Approach Based Myelin Quantification in Microscopic Fluorescence Images

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