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Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions.

ABSTRACT: Multiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease severity warrants urgent development of disease-modifying therapy, but the disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions (GCIs), which are insoluble ?-synuclein accumulations within oligodendrocytes (OLGs). Thus, preventive strategies against GCI formation may suppress disease progression. However, although numerous studies have tried to elucidate the molecular pathogenesis of GCI formation, difficulty remains in understanding the pathological interaction between the two pivotal aspects of GCIs; ?-synuclein and OLGs. The difficulty originates from several enigmas: 1) what triggers the initial generation and possible propagation of pathogenic ?-synuclein species? 2) what contributes to OLG-specific accumulation of ?-synuclein, which is abundantly expressed in neurons but not in OLGs? and 3) how are OLGs and other glial cells affected and contribute to neurodegeneration? The primary pathogenesis of GCIs may involve myelin dysfunction and dyshomeostasis of the oligodendroglial cellular environment such as autophagy and iron metabolism. We have previously reported that oligodendrocyte precursor cells are more prone to develop intracellular inclusions in the presence of extracellular fibrillary ?-synuclein. This finding implies a possibility that the propagation of GCI pathology in MSA brains is mediated through the internalization of pathological ?-synuclein into oligodendrocyte precursor cells. In this review, in order to discuss the pathogenesis of GCIs, we will focus on the composition of neuronal and oligodendroglial inclusions in synucleinopathies. Furthermore, we will introduce some hypotheses on how ?-synuclein pathology spreads among OLGs in MSA brains, in the light of our data from the experiments with primary oligodendrocyte lineage cell culture. While various reports have focused on the mysterious source of ?-synuclein in GCIs, insights into the mechanism which regulates the uptake of pathological ?-synuclein into oligodendroglial cells may yield the development of the disease-modifying therapy for MSA. The interaction between glial cells and ?-synuclein is also highlighted with previous studies of post-mortem human brains, cultured cells, and animal models, which provide comprehensive insight into GCIs and the MSA pathomechanisms.

SUBMITTER: Kaji S

PROVIDER: S-EPMC7025408 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions.

Kaji Seiji S Maki Takakuni T Ishimoto Tomoyuki T Yamakado Hodaka H Takahashi Ryosuke R

Translational neurodegeneration 20200217

Multiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease severity warrants urgent development of disease-modifying therapy, but the disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions (GCIs), which are insoluble α-synuclein accumulations within oligodendrocytes (OLGs). Thus, preventive strategies against GCI formation may suppress disease progression. However, although numer ...[more]

PMID: 32095235

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Project description:α-Synucleinopathies are spreading neurodegenerative disorders characterized by the intracellular accumulation of insoluble aggregates populated by α-Synuclein (α-Syn) fibrils. In Parkinson's disease (PD) and dementia with Lewy bodies, intraneuronal α-Syn aggregates are referred to as Lewy bodies in the somata and as Lewy neurites in the neuronal processes. In multiple system atrophy (MSA) α-Syn aggregates are also found within mature oligodendrocytes (OLs) where they form Glial Cytoplasmic Inclusions (GCIs). However, the origin of GCIs remains enigmatic: (i) mature OLs do not express α-Syn, precluding the seeding and the buildup of inclusions and (ii) the artificial overexpression of α-Syn in OLs of transgenic mice results in a burden of soluble phosphorylated α-Syn but fails to form α-Syn fibrils. In contrast, mass spectrometry of α-Syn fibrillar aggregates from MSA patients points to the neuronal origin of the proteins intimately associated with the fibrils within the GCIs. This suggests that GCIs are preassembled in neurons and only secondarily incorporated into OLs. Interestingly, we recently isolated a synthetic human α-Syn fibril strain (1B fibrils) capable of seeding a type of neuronal inclusion observed early and specifically during MSA. Our goal was thus to investigate whether the neuronal α-Syn pathology seeded by 1B fibrils could eventually be transmitted to OLs to form GCIs in vivo. After confirming that mature OLs did not express α-Syn to detectable levels in the adult mouse brain, a series of mice received unilateral intra-striatal injections of 1B fibrils. The resulting α-Syn pathology was visualized using phospho-S129 α-Syn immunoreactivity (pSyn). We found that even though 1B fibrils were injected unilaterally, many pSyn-positive neuronal somas were present in layer V of the contralateral perirhinal cortex after 6 weeks. This suggested a fast retrograde spread of the pathology along the axons of crossing cortico-striatal neurons. We thus scrutinized the posterior limb of the anterior commissure, i.e., the myelinated interhemispheric tract containing the axons of these neurons: we indeed observed numerous pSyn-positive linear Lewy Neurites oriented parallel to the commissural axis, corresponding to axonal segments filled with aggregated α-Syn, with no obvious signs of OL α-Syn pathology at this stage. After 6 months however, the commissural Lewy neurites were no longer parallel but fragmented, curled up, sometimes squeezed in-between two consecutive OLs in interfascicular strands, or even engulfed inside OL perikarya, thus forming GCIs. We conclude that the 1B fibril strain can rapidly induce an α-Syn pathology typical of MSA in mice, in which the appearance of GCIs results from the pruning of diseased axonal segments containing aggregated α-Syn.

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Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions.

Publications

Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions.

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