α-Synuclein-positive structures induced in leupeptin-infused rats

Nakajima, Tatsuo; Takauchi, S.; Ohara, Kazuhiko; Kokai, Masahiro; Nishii, Ryuichi; Maeda, Seishi; Takanaga, Akinori; Tanaka, Tomoaki; Takeda, Masatoshi; Seki, Makoto; Morita, Yoshifumi

doi:10.1016/j.brainres.2005.01.099

Cited by 12 publications

(10 citation statements)

References 31 publications

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“…This is consistent with recent studies showing that α-syn aggregates are cleared via autophagy and that alterations in the lysosomal pathway might participate in the mechanisms of α-syn-mediated neurodegeneration (Stefanis et al, 2001; Meredith et al, 2002; Webb et al, 2003; Cuervo et al, 2004; Rideout et al, 2004; Nakajima et al, 2005; Rockenstein et al, 2005b). Mutant forms of α-syn found in familial PD patients have been shown to block autophagy and α-syn contains a consensus sequence for CMA targeting (Cuervo et al, 2004).…”

Section: Discussionsupporting

confidence: 93%

Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in α-Synuclein Models of Parkinson's and Lewy Body Diseases

Spencer¹,

Potkar²,

Trejo³

et al. 2009

J. Neurosci.

534

455

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Section: Discussionsupporting

confidence: 93%

Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in α-Synuclein Models of Parkinson's and Lewy Body Diseases

Spencer¹,

Potkar²,

Trejo³

et al. 2009

J. Neurosci.

534

455

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“…This may lead to the formation of enlarged and atypical AV‐like structures (153). Consistent with these studies, recent evidence in cell‐based models of PD‐like pathology indicate that alterations in lysosomal functioning and autophagy might participate in the mechanisms of α‐syn‐mediated neurodegeneration (22, 29, 117, 119, 137, 139, 155).…”

Section: Alterations In Autophagy In α‐Synucleinopathiessupporting

confidence: 59%

Autophagy in Dementias

et al. 2011

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Dementias are a varied group of disorders typically associated with memory loss, impaired judgment and/or language and by symptoms affecting other cognitive and social abilities to a degree that interferes with daily functioning. Alzheimer’s disease (AD) is the most common cause of a progressive dementia, followed by dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia (VaD) and HIV associated neurocognitive disorders (HAND). The pathogenesis of this group of disorders has been linked to the abnormal accumulation of proteins in the brains of affected individuals, which in turn has been related to deficits in protein clearance. Autophagy is a key cellular protein clearance pathway with proteolytic cleavage and degradation via the ubiquitin-proteasome pathway representing another important clearance mechanism. Alterations in the levels of autophagy and the proteins associated with the autophagocytic pathway have been reported in various types of dementias. This review will examine recent literature across these disorders and highlight a common theme of altered autophagy across the spectrum of the dementias.

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“…Monoclonal anti-mouse glial fibrillary acidic protein (GFAP, 1:100) was from Roche (Vienna, Austria) and monoclonal anti-mouse CD11b (1:150) was from Serotec (Oxford, UK). All antibodies were applied successfully in immunohistochemistry before [15, 30, 32, 38]. The specificity of the immunostainings was verified in the current study by omitting primary antibodies and incubating sections with the full set of secondary antibodies.…”

Section: Methodsmentioning

confidence: 64%

Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

et al. 2012

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Multiple system atrophy (MSA) is a progressive late onset neurodegenerative a-synucleinopathy with unclear pathogenesis. Recent genetic and pathological studies support a central role of a-synuclein (aSYN) in MSA pathogenesis. Oligodendroglial cytoplasmic inclusions of fibrillar aSYN and dysfunction of the ubiquitinproteasome system are suggestive of proteolytic stress in this disorder. To address the possible pathogenic role of oligodendroglial aSYN accumulation and proteolytic failure in MSA we applied systemic proteasome inhibition (PSI) in transgenic mice with oligodendroglial human aSYN expression and determined the presence of MSAlike neurodegeneration in this model as compared to wildtype mice. PSI induced open field motor disability in transgenic aSYN mice but not in wild-type mice. The motor phenotype corresponded to progressive and selective neuronal loss in the striatonigral and olivopontocerebellar systems of PSI-treated transgenic aSYN mice. In contrast no neurodegeneration was detected in PSI-treated wildtype controls. PSI treatment of transgenic aSYN mice was associated with significant ultrastructural alterations including accumulation of fibrillar human aSYN in the cytoplasm of oligodendroglia, which resulted in myelin disruption and demyelination characterized by increased g-ratio. The oligodendroglial and myelin pathology was accompanied by axonal degeneration evidenced by signs of mitochondrial stress and dysfunctional axonal transport in the affected neurites. In summary, we provide new evidence supporting a primary role of proteolytic failure and suggesting a neurodegenerative pathomechanism related to disturbed oligodendroglial/myelin trophic support in the pathogenesis of MSA.

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α-Synuclein-positive structures induced in leupeptin-infused rats

Cited by 12 publications

References 31 publications

Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in α-Synuclein Models of Parkinson's and Lewy Body Diseases

Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in α-Synuclein Models of Parkinson's and Lewy Body Diseases

Autophagy in Dementias

Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

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