Mechanism of copper(II)-induced misfolding of Parkinson's disease protein

Rose, Frisco; Hodak, Miroslav; Bernholc, J.

doi:10.1038/srep00011

Cited by 77 publications

(72 citation statements)

References 38 publications

(56 reference statements)

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“…α-synuclein oligomerization and fibrillogenesis are also modulated byphosphorylation, C-terminal truncations and interactions with metals or pro-oxidant conditions (Breydo et al, 2012; Stefanis, 2012). A number of studies have reported that Cu interacts with α-synuclein accelerating aggregation and fibril formation and also modulating its membrane localization (Bortolus et al, 2010; Rasia et al, 2005; Rose et al, 2011; Uversky et al, 2001a; X. Wang et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways

Anandhan

Rodríguez-Rocha

Bohovych

et al. 2015

Neurobiology of Disease

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Gene multiplications or point mutations in alpha (α)-synuclein are associated with familial and sporadic Parkinson’s disease (PD). An increase in copper (Cu) levels has been reported in the cerebrospinal fluid and blood of PD patients, while occupational exposure to Cu has been suggested to augment the risk to develop PD. We aimed to elucidate the mechanisms by which α-synuclein and Cu regulate dopaminergic cell death. Short-term overexpression of WT or A53T α-synuclein had no toxic effect in human dopaminergic cells and primary midbrain cultures, but it exerted a synergistic effect on Cu-induced cell death. Cell death induced by Cu was potentiated by overexpression of the Cu transporter protein 1 (Ctr1) and depletion of intracellular glutathione (GSH) indicating that the toxic effects of Cu are linked to alterations in its intracellular homeostasis. Using the redox sensor roGFP, we demonstrated that Cu-induced oxidative stress was primarily localized in the cytosol and not in the mitochondria. However, α-synuclein overexpression had no effect on Cu-induced oxidative stress. WT or A53T α-synuclein overexpression exacerbated Cu toxicity in dopaminergic cells and yeast in the absence of α-synuclein aggregation. Cu increased autophagic flux and protein ubiquitination. Impairment of autophagy by overexpression of a dominant negative Atg5 form or inhibition of the ubiquitin/proteasome system (UPS) with MG132 enhanced Cu-induced cell death. However, only inhibition of the UPS stimulated the synergistic toxic effects of Cu and α-synuclein overexpression. Our results demonstrate that α-synuclein stimulates Cu toxicity in dopaminergic cells independent from its aggregation via modulation of protein degradation pathways.

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Section: Discussionmentioning

confidence: 99%

Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways

Anandhan

Rodríguez-Rocha

Bohovych

et al. 2015

Neurobiology of Disease

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“…The interplay between this variant and Cu 2+ was highly specific, because upon testing other relevant metals (24), no H50Q aSyn inclusions were observed. This unique synergy is not surprising, considering that the N-terminal region of aSyn in which H50 acts as a key metal anchoring residue constitutes the preferential binding interface for Cu 2+ (28,26,33,42). Previous studies, using other cell models, revealed that exposure to Cu 2+ promotes inclusion formation and toxicity in aSyn-expressing cells (43) and that the H50Q aSyn mutant exhibits a higher aggregation propensity when expressed intracellularly (44).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro NMR (28) and electron paramagnetic resonance (26,29) experiments have suggested that the ion binds in a square planar or tetrahedral distorted geometry, involving 2 or 3 N ligands and 2 or 1 O ligands, respectively (29)(30)(31). Models A and B (SI Appendix, SI Molecular Simulations) have been proposed in the literature (28,29,32). The Cu 2+ ion binds to the H50 side chain in both of them.…”

Section: Resultsmentioning

confidence: 99%

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

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

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Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.α-synuclein | copper | H50Q mutation | inclusions | protein aggregation

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“…Excess free Cu is toxic (5,6). Imbalance in cerebral Cu homeostasis plays a role in the pathogenesis of Alzheimer's disease (AD), and possibly other neurodegenerative diseases (7,8). Increased Cu levels in plasma and/or brain have been associated with AD (9)(10)(11)(12).…”

mentioning

confidence: 99%

Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance

Singh

Sagare

Coma

et al. 2013

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

227

158

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Significance The causes of the sporadic form of Alzheimer’s disease (AD) are unknown. In this study we show that copper (Cu) critically regulates low-density lipoprotein receptor-related protein 1–mediated Aβ clearance across the blood–brain barrier (BBB) in normal mice. Faulty Aβ clearance across the BBB due to increased Cu levels in the aging brain vessels may lead to accumulation of neurotoxic Aβ in brains. In a mouse model of AD low levels of Cu also influences Aβ production and neuroinflammation. Our study suggests that Cu may also increase the severity of AD.

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Mechanism of copper(II)-induced misfolding of Parkinson's disease protein

Cited by 77 publications

References 38 publications

Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways

Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance

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