Cellular pathology in multiple system atrophy

Wakabayashi, Keiji; Takahashi, Hitoshi

doi:10.1111/j.1440-1789.2006.00713.x

Cited by 143 publications

(139 citation statements)

References 89 publications

(186 reference statements)

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“…The histological hallmarks of MSA are the neuronal loss and the presence of argyrophilic fibrillary inclusions in the oligodendrocytes, referred to as glial cytoplasmic inclusions (GCIs), which are also known as Papp-Lantos bodies [99], the major component of which is fibrillated α-synuclein [100,101].…”

Section: Dementia With Lewy Bodies (Dlb)mentioning

confidence: 99%

Amyloidogenesis of Natively Unfolded Proteins

Uversky

2008

CAR

174

152

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Aggregation and subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. The accumulated data support the model where protein fibrillogenesis proceeds via the formation of a relatively unfolded amyloidogenic conformation, which shares many structural properties with the pre-molten globule state, a partially folded intermediate first found during the equilibrium and kinetic (un)folding studies of several globular proteins and later described as one of the structural forms of natively unfolded proteins. The flexibility of this structural form is essential for the conformational rearrangements driving the formation of the core cross-beta structure of the amyloid fibril. Obviously, molecular mechanisms describing amyloidogenesis of ordered and natively unfolded proteins are different. For ordered protein to fibrillate, its unique and rigid structure has to be destabilized and partially unfolded. On the other hand, fibrillogenesis of a natively unfolded protein involves the formation of partially folded conformation; i.e., partial folding rather than unfolding. In this review recent findings are surveyed to illustrate some unique features of the natively unfolded proteins amyloidogenesis.

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Section: Dementia With Lewy Bodies (Dlb)mentioning

confidence: 99%

Amyloidogenesis of Natively Unfolded Proteins

Uversky

2008

CAR

174

152

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“…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).…”

mentioning

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

131

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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“…Based on these findings, MSA has been considered a primary oligodendrogliopathy with GCI accumulation causing oligodendroglia-myelin degeneration [106,136,192,205]. Early myelin alterations in MSA brains have been demonstrated recently by the presence of altered myelin basic protein and p25alpha [205].…”

Section: Neuropathologymentioning

confidence: 96%

“…However, some researchers propose that this pathogenic oligodendroglial mechanism could occur synergistically with a direct neuronal alteration (as in a neuronal synucleinopathy), since a primary nonfibrillar and fibrillar alphasynuclein accumulation seems to also be present in neurons [192,212].…”

Section: Neuropathologymentioning

confidence: 98%

Recent developments in multiple system atrophy

Wenning

Stefanova

2009

J Neurol

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Multiple system atrophy (MSA) is a rare late onset neurodegenerative disorder which presents with autonomic failure and a complicated motor syndrome including atypical parkinsonism, ataxia and pyramidal signs. MSA is a glial alpha-synucleinopathy with rapid progression and currently poor therapeutic management. This paper reviews the clinical features, natural history and novel diagnostic criteria for MSA as well as contemporary knowledge on pathogenesis based on evidence from neuropathological studies and experimental models. An outline of the rationale for managing symptomatic deterioration in MSA is provided together with a summary of novel experimental therapeutic approaches to decrease disease progression.

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Cellular pathology in multiple system atrophy

Cited by 143 publications

References 89 publications

Amyloidogenesis of Natively Unfolded Proteins

Amyloidogenesis of Natively Unfolded Proteins

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

Recent developments in multiple system atrophy

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