In Situ and in Vitro Study of Colocalization and Segregation of α-Synuclein, Ubiquitin, and Lipids in Lewy Bodies

Gai, Wei; Yuan, Huiyang; Li, X.Q.; Power, J.T.H.; Blumbergs, Peter; Jensen, Poul Henning

doi:10.1006/exnr.2000.7527

Cited by 258 publications

(232 citation statements)

References 44 publications

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“…The pattern of ␣-synuclein aggregate in our model, containing mitochondria, has been recognized in human disease and is considered to be an early form of Lewy body (Gai et al, 2000). The paucity of literature on mitochondria in human disease led us to substantiate our findings by EM analysis of substantia nigra from PD patients.…”

Section: Mitochondrial Involvement In Inclusion Body Formationsupporting

confidence: 52%

“…Impaired 26S proteasomal function causes neurodegeneration and intraneuronal inclusion body formation, reflecting early forms of human Lewy bodies described as homogeneous Lewy bodies (Gai et al, 2000) or pale bodies (Dale et al, 1992). The intraneuronal inclusions in our mouse model are different from those seen in PD or DLB because the classical concentric Lewy body does not form.…”

Section: Discussionmentioning

confidence: 85%

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Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies

Bedford

Hay²,

Devoy³

et al. 2008

J. Neurosci.

295

254

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Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinson's disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and ␣-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinson's disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.

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Section: Mitochondrial Involvement In Inclusion Body Formationsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 85%

Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies

Bedford

Hay²,

Devoy³

et al. 2008

J. Neurosci.

295

254

View full text Add to dashboard Cite

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“…Parkinson's disease (PD) pathology is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the formation of Lewy bodies in these and other neurons (Braak et al, 2003;Fornai et al, 2003;Forno, 1996;Gai et al, 2000;Spillantini et al, 1997). Lewy bodies are intracellular inclusions largely composed of aggregated proteins, notably asynuclein.…”

mentioning

confidence: 99%

From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinson’s Disease Models

Wise

Cannon

2016

Toxicol. Sci.

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Parkinson's disease (PD) is a progressive neurodegenerative disease that affects $5 million people around the world. PD etiopathogenesis is poorly understood and curative or disease modifying treatments are not available. Mechanistic studies have identified numerous pathogenic pathways that overlap with many other neurodegenerative diseases. Mutations in the protein optineurin (OPTN) have recently been identified as causative factors for glaucoma and amyotrophic lateral sclerosis. OPTN has multiple recognized roles in neurons, notably in mediating autophagic flux, which has been found to be disrupted in most neurodegenerative diseases. OPTN þ aggregates have preliminarily been identified in cytoplasmic inclusions in numerous neurodegenerative diseases, however, whether OPTN has a role in PD pathogenesis has yet to be tested. Thus, we chose to test the hypothesis that OPTN expression and localization would be modulated in pre-clinical PD models. To test our hypothesis, we characterized midbrain OPTN expression in normal rats and in a rat rotenone PD model. For the first time, we show that OPTN is enriched in dopamine neurons in the midbrain, and its expression is modulated by rotenone treatment in vivo. Here, animals were sampled at time-points both prior to overt neurodegeneration and after severe behavioral deficits, where a lesion to the nigrostriatal dopamine system is present. The effect and magnitude of OPTN expression changes are dependent on duration of treatment. Furthermore, OPTN colocalizes with LC3 (autophagic vesicle marker) and alpha-synuclein positive puncta in rotenone-treated animals, potentially indicating an important role in autophagy and PD pathogenesis.

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“…7 Ela parece participar de forma importante na patogênese de doenças neurodegenerativas, agregando-se para formar inclusões intracelulares. 8 Essas inclusões ocorrem nos oligodendrócitos e são patognomônicas de várias doenças neurodegenerativas, como atrofia de múltiplos sistemas, DCL e doença de Parkinson (DP).…”

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“…A segregação da alfa-sinucleína para a periferia do CL é consistente com a hipótese de que ela é constantemente depositada. 7,11 Os CL são achados em diversas outras doenças (Tabela 1), embora sejam caracteristicamente associados à DP idiopática. unificou os critérios e definiu suas características principais (Tabela 2).…”

unclassified

Demência com corpúsculos de Lewy: uma entidade distinta com tratamento específico?

Tatsch¹,

Nitrini²,

Neto³

2002

Rev. Bras. Psiquiatr.

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KeywordsA demência com corpúsculos de Lewy (DCL), síndrome com curso flutuante, alucinações visuais, sinais parkinsonianos e hipersensibilidade a antipsicóticos, tem recebido crescente atenção nos últimos anos. Possui, desde 1995, critérios clínicos e neuropatológicos que permitem diagnosticá-la desde o início. A combinação de déficits colinérgico e dopaminérgico requer tratamentos cautelosos. Uso excessivo de medicações dopaminérgicas (L-dopa), antidopaminérgicas (antipsicóticos) ou anticolinérgicas (antipsicóticos ou anti-parkinsonianos) pode complicar o quadro, piorando sintomas cognitivos, psicóticos e extrapiramidais.

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In Situ and in Vitro Study of Colocalization and Segregation of α-Synuclein, Ubiquitin, and Lipids in Lewy Bodies

Cited by 258 publications

References 44 publications

Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies

Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies

From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinson’s Disease Models

Demência com corpúsculos de Lewy: uma entidade distinta com tratamento específico?

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