Dataset Information

Replication of multiple system atrophy prions in primary astrocyte cultures from transgenic mice expressing human ?-synuclein.

ABSTRACT: Glial cytoplasmic inclusions (GCIs) containing aggregated and hyperphosphorylated ?-synuclein are the signature neuropathological hallmark of multiple system atrophy (MSA). Native ?-synuclein can adopt a prion conformation that self-propagates and spreads throughout the brain ultimately resulting in neurodegeneration. A growing body of evidence argues that, in addition to oligodendrocytes, astrocytes contain ?-synuclein inclusions in MSA and other ?-synucleinopathies at advanced stages of disease. To study the role of astrocytes in MSA, we added MSA brain homogenate to primary cultures of astrocytes from transgenic (Tg) mouse lines expressing human ?-synuclein. Astrocytes from four Tg lines, expressing either wild-type or mutant (A53T or A30P) human ?-synuclein, propagated and accumulated ?-synuclein prions. Furthermore, we found that MSA-infected astrocytes formed two morphologically distinct ?-synuclein inclusions: filamentous and granular. Both types of cytoplasmic inclusions shared several features characteristic of ?-synuclein inclusions in synucleinopathies: hyperphosphorylation preceded by aggregation, ubiquitination, thioflavin S-positivity, and co-localization with p62. Our findings demonstrate that human ?-synuclein forms distinct inclusion morphologies and propagates within cultured Tg astrocytes exposed to MSA prions, indicating that ?-synuclein expression determines the tropism of inclusion formation in certain cells. Thus, our work may prove useful in elucidating the role of astrocytes in the pathogenic mechanisms that feature in neurodegeneration caused by MSA prions.

SUBMITTER: Krejciova Z

PROVIDER: S-EPMC6526619 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Replication of multiple system atrophy prions in primary astrocyte cultures from transgenic mice expressing human α-synuclein.

Krejciova Zuzana Z Carlson George A GA Giles Kurt K Prusiner Stanley B SB

Acta neuropathologica communications 20190520 1

Glial cytoplasmic inclusions (GCIs) containing aggregated and hyperphosphorylated α-synuclein are the signature neuropathological hallmark of multiple system atrophy (MSA). Native α-synuclein can adopt a prion conformation that self-propagates and spreads throughout the brain ultimately resulting in neurodegeneration. A growing body of evidence argues that, in addition to oligodendrocytes, astrocytes contain α-synuclein inclusions in MSA and other α-synucleinopathies at advanced stages of diseas ...[more]

PMID: 31109379

Similar Datasets

Project description:α-Synuclein (αSN) in human is tightly linked both neuropathologically and genetically to Parkinson's disease (PD) and related disorders. Disease-causing properties in vivo of the wildtype mouse ortholog (mαSN), which carries a threonine at position 53 like the A53T human mutant version that is genetically linked to PD, were never reported. To this end we generated mouse lines that express mαSN in central neurons at levels reaching up to six-fold compared to endogenous mαSN. Unlike transgenic mice expressing human wildtype or mutant forms of αSN, these mαSN transgenic mice showed pronounced ubiquitin immunopathology in spinal cord and brainstem. Isoelectric separation of mαSN species revealed multiple isoforms including two Ser129-phosphorylated species in the most severely affected brain regions. Neuronal Ser129-phosphorylated αSN occurred in granular and small fibrillar aggregates and pathological staining patterns in neurites occasionally revealed a striking ladder of small alternating segments staining either for Ser129-phosphorylated αSN or ubiquitin but not both. Axonal degeneration in long white matter tracts of the spinal cord, with breakdown of myelin sheaths and degeneration of neuromuscular junctions with loss of integrity of the presynaptic neurofilament network in mαSN transgenic mice, was similar to what we have reported for mice expressing human αSN wildtype or mutant forms. In hippocampal neurons, the mαSN protein accumulated and was phosphorylated but these neurons showed no ubiquitin immunopathology. In contrast to the early-onset motor abnormalities and muscle weakness observed in mice expressing human αSN, mαSN transgenic mice displayed only end-stage phenotypic alterations that manifested alongside with neuropathology. Altogether these findings show that increased levels of wildtype mαSN does not induce early-onset behavior changes, but drives end-stage pathophysiological changes in murine neurons that are strikingly similar to those evoked by expression of human wildtype or mutant forms.

Dataset Information

Replication of multiple system atrophy prions in primary astrocyte cultures from transgenic mice expressing human ?-synuclein.

Publications

Replication of multiple system atrophy prions in primary astrocyte cultures from transgenic mice expressing human α-synuclein.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets