Neuronal and glial accumulation of α- and β-synucleins in human lipidoses

Suzuki, Kyoko; Iseki, Eizo; Togo, Takashi; Yamaguchi, Akira; Katsuse, Omi; Katsuyama, Kayoko; Kanzaki, Seiichi; Shiozaki, Kazumasa; Kawanishi, Chiaki; Yamashita, Sumimasa; Tanaka, Yukichi; Yamanaka, Shōji; Hirayasu, Yoshio

doi:10.1007/s00401-007-0264-z

Cited by 80 publications

(63 citation statements)

References 31 publications

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“…Lysosomal activity decreases with aging, and mutations in lysosomal hydrolases cause neurodegeneration in several inherited lysosomal storage disorders (23,24). Moreover, neuronal and glial accumulation of ␣-synuclein was observed in several human lipidoses and a mouse model of GM2 gangliosidosis (25,26). Recently, in yeast, Caenorhabditis elegans, and rat midbrain dopamine neurons, ␣-synuclein toxicity was shown to be antagonized by ATP13A2/PARK9 (27), whose gene product is localized in the lysosome and suspected in lysosomal function (28).…”

Section: Discussionmentioning

confidence: 99%

Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein

Desplats

Lee

Bae

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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1,266

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Fig. 2.Transformants releasing E␤C suffered less damage than control lines when EPNs were present. (A) Root damage measured on plants that had received neither WCR eggs nor nematodes was minimal, and there was no difference between transformed and nontransformed plants (n ϭ 5, P ϭ 0.87). (B) Root damage on plants that received only WCR eggs, but no nematodes, was substantial. Again, no significant difference was found between the transformed and nontransformed plants (n ϭ 5, P ϭ 0.18). (C) In plots that received WCR eggs and H. megidis, roots from transformed plants (pooled) had significantly less damage than roots from control lines (n ϭ 30, P ϭ 0.007). Approximately one-quarter of the transformed plants were found not to emit E␤C. Removing these plants from the statistical analysis did not significantly affect the results. The letters above the bars indicate significant differences within a graph. Error bars indicate standard errors.

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Section: Discussionmentioning

confidence: 99%

Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein

Desplats

Lee

Bae

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

1,326

1,266

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“…The α‐synuclein gene, SNCA, is mainly expressed in neurons but also in glial cells, and is specially expressed in neurolipidoses such as Sandhoff disease, Tay‐Sachs disease, metachromatic leukodystrophy, β‐galactosialidosis, and adrenoleukodystrophy (Suzuki et al, 2007). In the present study, we observed a significant up‐regulation of α‐synuclein in the three brain regions, as shown in Figure 7A.…”

Section: Resultsmentioning

confidence: 99%

Identification of new markers for neurodegeneration process in the mouse model of Sly disease as revealed by expression profiling of selected genes

Richard

Arfi

Rhinn

et al. 2008

J of Neuroscience Research

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Sly disease (MPS VII) is an autosomal-recessive lysosomal storage disorder resulting from beta-glucuronidase deficiency, which is characterized by a severe neurological impairment. MPS VII mice accumulate undegraded glycosaminoglycans and mimic the human neurodegenerative disorder, thus appearing to be an excellent tool to delineate disease pathogenesis. The relationship between abnormal glycosaminoglycan storage and neurodysfunction is not yet well understood, but inflammatory components can be involved, as in several neurological lysosomal disorders. Inflammatory biomarkers are thus good candidates to evaluate the neurodegeneration state of the disease. By using quantitative polymerase chain reaction, we have compared the expression of selected genes of normal and MPS VII cerebral tissues, focusing on inflammation and apoptosis-related genes. The gene expression was evaluated in various brain regions throughout the lifetime of the animals. We have identified a specific expression profile for 27 genes, which was strongly marked in the central nervous system posterior region. Finally, new Sly disease markers were characterized that reflect neurological deterioration state, and that can be used in preclinical follow-up studies.

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“…20 Further, Lewy body-like structures were found in a wide range of LSDs and related disorders, including Niemann-Pick C1 disease, Tay-Sachs disease, metachromatic leukodystrophy, ␤-galactosialidosis, and adrenoleukodystrophy. 21,22 Despite accumulating histological data, the role of increased syn proteins in the pathogenesis of the LSDs is unclear.…”

mentioning

confidence: 99%

Protective Role of Endogenous Gangliosides for Lysosomal Pathology in a Cellular Model of Synucleinopathies

Wei

Fujita

Nakai

et al. 2009

The American Journal of Pathology

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Gangliosides may be involved in the pathogenesis of Parkinson's disease and related disorders, although the precise mechanisms governing this involvement remain unknown. In this study, we determined whether changes in endogenous ganglioside levels affect lysosomal pathology in a cellular model of synucleinopathy. For this purpose, dementia with Lewy body-linked P123H ␤-synuclein (␤-syn) neuroblastoma cells transfected with ␣-synuclein were used as a model system because these cells were characterized as having extensive formation of lysosomal inclusions bodies. Treatment of these cells with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthase, resulted in various features of lysosomal pathology, including compromised lysosomal activity, enhanced lysosomal membrane permeabilization, and increased cytotoxicity. Consistent with these findings, expression levels of lysosomal membrane proteins, ATP13A2 and LAMP-2, were significantly decreased, and electron microscopy demonstrated alterations in the lysosomal membrane structures. Furthermore, the accumulation of both P123H ␤-syn and ␣-synuclein proteins was significant in PDMP-treated cells because of the suppressive effect of PDMP on the autophagy pathway. Finally, the detrimental effects of PDMP on lysosomal pathology were significantly ameliorated by the addition of gangliosides to the cultured cells. These data suggest that endogenous gangliosides may play protective roles against the lysosomal pathology of synucleinopathies. (Am J

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Neuronal and glial accumulation of α- and β-synucleins in human lipidoses

Cited by 80 publications

References 31 publications

Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein

Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein

Identification of new markers for neurodegeneration process in the mouse model of Sly disease as revealed by expression profiling of selected genes

Protective Role of Endogenous Gangliosides for Lysosomal Pathology in a Cellular Model of Synucleinopathies

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