Multiple system atrophy: α‐synuclein and neuronal degeneration

Yoshida, Mari

doi:10.1111/j.1440-1789.2007.00841.x

Cited by 158 publications

(66 citation statements)

References 67 publications

(167 reference statements)

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“…Thus, it may better reflect the molecular events occurring in MSA as compared with PD and dementia with Lewy bodies and may, therefore, involve different kinases, although ␣-syn present in inclusions in both types of diseases is strongly phosphorylated at Ser-129 (64,65).…”

Section: Discussionmentioning

confidence: 99%

α-Synuclein Aggregation and Ser-129 Phosphorylation-dependent Cell Death in Oligodendroglial Cells

Kragh

Lund

Febbraro

et al. 2009

Journal of Biological Chemistry

129

163

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Multiple system atrophy is a neurodegenerative disorder characterized by accumulation of aggregated Ser-129-phosphorylated ␣-synuclein in oligodendrocytes. p25␣ is an oligodendroglial protein that potently stimulates ␣-synuclein aggregation in vitro. To model multiple system atrophy, we coexpressed human p25␣ and ␣-synuclein in the rat oligodendroglial cell line OLN-93 and observed a cellular response characterized by a fast retraction of microtubules from the cellular processes to the perinuclear region followed by a protracted development of apoptosis. This response was dependent on phosphorylation at Ser-129 in ␣-synuclein as demonstrated by site-directed mutagenesis. Treatment of the cells with the kinase inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H benzimidazole that targets kinases like casein kinase 2, and polo-like kinases abrogated the toxicity. The polo-like kinase inhibitor BI 2536 caused apoptosis in the model. Ser-129 phosphorylation was linked to the formation of phosphorylated oligomers detectable by immunoblotting, and their formation was inhibited by 2-dimethylamino-4,5,6,7-tetrabromo-1H benzimidazole. The process of microtubule retraction was also dependent on aggregation as demonstrated by the protective effect of treating the cells with the specific peptide inhibitor of ␣-synuclein aggregation ASI1D and the non-selective inhibitors Congo Red and baicalein. The fast microtubule retraction was followed by the development of the apoptotic markers: activated caspase-3, phosphatidylserine externalization, nuclear condensation, and fragmentation. These markers could all be blocked by the inhibitors of phosphorylation, aggregation, and caspase-3. Hence, the model predicts that both Ser-129 phosphorylation and aggregation control the toxic ␣-syn pathway in oligodendroglial cells and may represent therapeutic intervention points in multiple system atrophy.2 is a soluble protein localized in presynaptic terminals (1). It accumulates as insoluble aggregates in cytoplasmic inclusions in ␣-synucleinopathies, among which Parkinson disease (PD) and dementia with Lewy bodies are the predominant members (2-4). Mutations in the ␣-syn gene leading to amino acid substitutions (A30P, A53T, and E46K) (5-7), and multiplications of the ␣-syn gene (8, 9) are associated with rare familial forms of PD and Lewy bodies.Multiple system atrophy (MSA) represents a special case among the ␣-synucleinopathies. The histological hallmark of MSA is the presence of ␣-syn-containing inclusions in oligodendrocytes, referred to as glial cytoplasmic inclusions (10, 11). Clinically, MSA presents with parkinsonism, ataxia, and autonomic failure, which signify the wide distribution of the degenerative processes (12). The degeneration of oligodendrocytes has been studied using transgenic mice expressing human ␣-syn under the control of oligodendroglial promoters (13-15). These models have demonstrated that expression of ␣-syn in oligodendrocytes results in formation of ␣-syn-containing glial cytoplasmic inclusions, myelin damage, and c...

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Section: Discussionmentioning

confidence: 99%

α-Synuclein Aggregation and Ser-129 Phosphorylation-dependent Cell Death in Oligodendroglial Cells

Kragh

Lund

Febbraro

et al. 2009

Journal of Biological Chemistry

129

163

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“…The combination of dementia with a movement disorder raises the possibility of multiple system atrophy [33], Parkinson’s disease [34] and Huntington’s disease (HD) [35]. Preserved autonomic function makes multiple system atrophy unlikely, retinal degeneration is not seen in Parkinson’s disease and Huntington’s disease will have an autosomal dominant family history.…”

Section: Discussionmentioning

confidence: 99%

The Neurological Presentation of Ceruloplasmin Gene Mutations

et al. 2008

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Aceruloplasminemia is an autosomal recessive disorder of iron metabolism resulting from mutations of the ceruloplasmin gene. To better define the neurological phenotype of aceruloplasminemia we reviewed reports of published cases and sought details of unpublished ones. We identified 32 published reports and 1 unpublished case. The age at diagnosis ranged from 16 to 71 years with a mean of 51. For the 28 homozygous cases the most common presentation was with cognitive impairment (12/28, 42%) accompanied by craniofacial dyskinesia (8/28, 28%), cerebellar ataxia (13/28, 46%) and retinal degeneration (21/28, 75%). Four heterozygotes presented with cerebellar signs or tremor, whilst 1 had chorea-athetosis. There were no genotype-phenotype associations, but homozygotes tended to have severer disease.

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“…In histopathological examinations, cellular loss and gliosis were revealed in the putamen, caudate nucleus, globus pallidus, substantia nigra, locus ceruleus, inferior olives, cerebellar Purkinje cells, substantia nigra, pontine nuclei, intermediolateral cell columns and Onuf's nucleus of the spinal cord [3,4]. The glial cytoplasmic inclusions formed by fibrillar alpha-synuclein proteins in oligodenendroglial cells were found in the brains of MSA patients regardless of the clinical presentation (striatonigral degeneration [SND], olivo-ponto-cerebellar atrophy [OPCA], Shy-Drager syndrome [SDS]) [5,6].…”

Section: Introductionmentioning

confidence: 99%