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Suppression of dynamin GTPase decreases ?-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy.

ABSTRACT:

Background

The intracellular deposition of misfolded proteins is a common neuropathological hallmark of most neurodegenerative disorders. Increasing evidence suggests that these pathogenic proteins may spread to neighboring cells and induce the propagation of neurodegeneration.

Results

In this study, we have demonstrated that ?-synuclein (?SYN), a major constituent of intracellular inclusions in synucleinopathies, was taken up by neuronal and oligodendroglial cells in both a time- and concentration-dependent manner. Once incorporated, the extracellular ?SYN was immediately assembled into high-molecular-weight oligomers and subsequently formed cytoplasmic inclusion bodies. Furthermore, ?SYN uptake by neurons and cells of the oligodendroglial lineage was markedly decreased by the genetic suppression and pharmacological inhibition of the dynamin GTPases, suggesting the involvement of the endocytic pathway in this process.

Conclusions

Our findings shed light on the mode of ?SYN uptake by neuronal and oligodendroglial cells and identify therapeutic strategies aimed at reducing the propagation of protein misfolding.

SUBMITTER: Konno M

PROVIDER: S-EPMC3479026 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Publications

Suppression of dynamin GTPase decreases α-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy.

Konno Masatoshi M Hasegawa Takafumi T Baba Toru T Miura Emiko E Sugeno Naoto N Kikuchi Akio A Fiesel Fabienne C FC Sasaki Tsutomu T Aoki Masashi M Itoyama Yasuto Y Takeda Atsushi A

Molecular neurodegeneration 20120814

<h4>Background</h4>The intracellular deposition of misfolded proteins is a common neuropathological hallmark of most neurodegenerative disorders. Increasing evidence suggests that these pathogenic proteins may spread to neighboring cells and induce the propagation of neurodegeneration.<h4>Results</h4>In this study, we have demonstrated that α-synuclein (αSYN), a major constituent of intracellular inclusions in synucleinopathies, was taken up by neuronal and oligodendroglial cells in both a time- ...[more]

PMID: 22892036

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Project description: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.