α-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells

Kaźmierczak, Anna; Strosznajder, Joanna B.; Adamczyk, Agata

doi:10.1016/j.neuint.2008.08.004

Cited by 55 publications

(64 citation statements)

References 66 publications

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“…Our previous findings indicated that ASN-induced mitochondrial dysfunction was responsible for elevated oxidative stress [6]. In agreement with these earlier findings, cytosolic ROS level assayed by the DCF method was significantly elevated in PC12 cells treated with extracellular ASN for 8 and 24 h as compared to control PC12 cells (Fig.…”

Section: Resultssupporting

confidence: 91%

“…Measurement of the free radicals level was carried out using fluorescent indicator 2′7'-dichlorofluorescein diacetate (DCFH-DA) (Cayman Chemical Company), as described previously [6]. DCFH-DA is intracellularly deacetylated to 2′7′-dichlorofluorescin (DCFH) and then oxidized by hydrogen peroxide to a fluorescent compound, 2′7'-dichlorofluorescein (DCF).…”

Section: Measurement Of Intracellular Free Radical Levelmentioning

confidence: 99%

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Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

et al. 2018

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α-Synuclein (ASN) and parkin, a multifunctional E3 ubiquitin ligase, are two proteins that are associated with the pathophysiology of Parkinson's disease (PD). Excessive release of ASN, its oligomerization, aggregation, and deposition in the cytoplasm contribute to neuronal injury and cell death through oxidative-nitrosative stress induction, mitochondrial impairment, and synaptic dysfunction. In contrast, overexpression of parkin provides protection against cellular stresses and prevents dopaminergic neural cell loss in several animal models of PD. However, the influence of ASN on the function of parkin is largely unknown. Therefore, the aim of this study was to investigate the effect of extracellular ASN oligomers on parkin expression, S-nitrosylation, as well as its activity. For these investigations, we used rat pheochromocytoma (PC12) cell line treated with exogenous oligomeric ASN as well as PC12 cells with parkin overexpression and parkin knock-down. The experiments were performed using spectrophotometric, spectrofluorometric, and immunochemical methods. We found that exogenous ASN oligomers induce oxidative/nitrosative stress leading to parkin Snitrosylation. Moreover, this posttranslational modification induced the elevation of parkin autoubiquitination and degradation of the protein. The decreased parkin levels resulted in significant cell death, whereas parkin overexpression protected against toxicity induced by extracellular ASN oligomers. We conclude that lowering parkin levels by extracellular ASN may significantly contribute to the propagation of neurodegeneration in PD pathology through accumulation of defective proteins as a consequence of parkin degradation.

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Section: Resultssupporting

confidence: 91%

Section: Measurement Of Intracellular Free Radical Levelmentioning

confidence: 99%

Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

et al. 2018

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“…Moreover, Parkinson patients might develop dementia and amyloid-␤-rich plaques. These overlapping disorders suggest that amyloid-␤ and ␣-synuclein might be associated (18 ). The occurrence of amyloid-␤ and ␣-synuclein in Lewy bodies also suggests that their accumulation might be related to mutual pathologic conditions.…”

Section: Discussionmentioning

confidence: 98%

Methylation Status and Neurodegenerative Markers in Parkinson Disease

Obeid

Schadt²,

Dillmann

et al. 2009

Clinical Chemistry

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Background: Increased concentrations of plasma total homocysteine (tHcy) have been associated with age-related diseases, including dementia, stroke, and Parkinson disease (PD). Methylation status might link Hcy metabolism to neurodegenerative proteins in patients with PD. Methods: We tested blood samples from 87 patients with PD (median age 68 years; 35 men) for tHcy, methylmalonic acid (MMA), vitamin B12, vitamin B6, folate, S-adenosyl methionine (SAM), S-adenosyl homocysteine (SAH), and amyloid-β(1–42). We collected citrate blood from a subset of 45 patients to prepare platelet-rich plasma, and we used washed platelets to prepare cell extracts for amyloid precursor protein (APP) and α-synuclein assays. We used brain parenchyma sonography to estimate the substantia nigra echogenic area in a subset of 59 patients. Results: Serum concentrations of tHcy were increased in PD patients (median 14.8 μmol/L). tHcy (β coefficient = −0.276) and serum creatinine (β = −0.422) were significant predictors of the ratio of SAM/SAH in plasma (P < 0.01). The plasma SAM/SAH ratio was a significant determinant for DemTect scores (β = 0.612, P = 0.004). Significant negative correlations were found between concentrations of SAH in plasma and platelet APP and between SAM and platelet α-synuclein. A larger echogenic area of the substantia nigra was related to higher serum concentrations of MMA (P = 0.016). Conclusions: Markers of neurodegeneration (APP, α-synuclein) are related to markers of methylation (SAM, SAH) in patients with PD. Better cognitive function was related to higher methylation potential (SAM/SAH ratio).

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“…There is indeed some evidence that PrP conversion to misfolded PrP Sc forms can increase the misprocessing of APP by increasing the activity of the so-called beta secretase, which cleaves APP to a extracellularly released fragment and a "C99" transmembrane domain (14). Asyn interactions with APP have also been shown to greatly increase the level of Abeta secretion from PC12 cells (121). Conversely, the observation that Abeta activates the srk family kinase Abl resulting in tau phosphorylation at sites crucial to disease-associated tau aggregation (34), is also consistent with the possibility that Abetainduced tau misprocessing may occur in the context of endosome formation.…”

Section: Misprocessing Of App To Abeta 1-42 In Early Endosomesmentioning

confidence: 99%

What is the Link Between Protein Aggregation and Interneuronal Lesion Propagation in Neurodegenerative Disease?

Hall¹

2011

Neurodegenerative Diseases - Processes, Prevention, Protection and Monitoring

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α-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells

Cited by 55 publications

References 66 publications

Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

Methylation Status and Neurodegenerative Markers in Parkinson Disease

What is the Link Between Protein Aggregation and Interneuronal Lesion Propagation in Neurodegenerative Disease?

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