Interactions between metals and α‐synuclein − function or artefact?

Brown, David R.

doi:10.1111/j.1742-4658.2007.05917.x

Cited by 54 publications

(47 citation statements)

References 83 publications

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“…Post-translational modifications of pro teins represent important molecular switches for regulating protein-protein and protein-ligand interactions and thus protein function in health and disease. The C-terminal region of a-syn has been implicated in the majority of a-syn interac tions with proteins (Fernandez et al, 2004;Gias son et al, 2003;Jensen et al, 1999) and metal ions (Brown, 2007;Paik et al, 1999). Therefore, trun cation and/or phosphorylation at single or multi ple sites is likely to influence a-syn affinity to proteins, metals and other ligands (e.g.…”

Section: Looking Beyond Aggregationmentioning

confidence: 99%

“…The C-terminus of a syn has been proposed to function as a solubilizing domain and contributes to a-syn's thermostability. The C-terminal region of a-syn has been implicated in the majority of a-syn interactions with proteins Fernandez et al, 2004;Giasson et al, 2003;Jensen et al, 1999), metal ions (Brown, 2007;Paik et al, 1999) and other ligands (e.g. dopamine and polyamines) and contains the majority of post-trans lational modification sites.…”

Section: Structural and Biochemical Properties Of A-synmentioning

confidence: 99%

“…However, in the presence of lipids, the N-terminal region adopts an a-helical conformation. Several factors have been shown to contribute to triggering the oligomerization and fibril formation by a-syn, including high protein concentrations, mutations, post-translational modifications and interactions with specific metals (Brown, 2007;Paik et al, 1999) and small molecules . Fibril formation by a-syn proceeds through series of discrete oligomeric intermediates, known as protofibrils of different sizes and morphologies, including spherical, annular and chain-like struc tures (Fig.…”

Section: Structural and Biochemical Properties Of A-synmentioning

confidence: 99%

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Role of post-translational modifications in modulating the structure, function and toxicity of α-synuclein

Oueslati

Fournier

Lashuel

2010

Progress in Brain Research

327

282

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A better understanding of the molecular and cellular determinants that influence the pathology of Parkinson's disease (PD) is essential for developing effective diagnostic, preventative and therapeutic strategies to treat this devastating disease. A number of post-translational modifications to a-syn are present within the Lewy bodies in the brains of affected patients and transgenic models of PD and related disorders. However, whether disease-associated a-syn post-translational modifications promote or inhibit a-syn aggregation and neurotoxicity in vivo remains unknown. Herein, we summarize and discuss the major disease-associated post-translational modifications (phosphorylation, truncation and ubiquitination) and present our current understanding of the effect of these modifications on a-syn aggregation and toxicity. Elucidating the molecular mechanisms underlying post-translation modifications of a-syn and the consequences of such modifications on the biochemical, structural, aggregation and toxic properties of the protein is essential for unravelling the molecular basis of its function(s) in health and disease. Furthermore, the identification of the natural enzymes involved in regulating the post-translational modifications of a-synuclein will yield novel and more tractable therapeutic targets to treat PD and related synucleinopathies.

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Section: Looking Beyond Aggregationmentioning

confidence: 99%

Section: Structural and Biochemical Properties Of A-synmentioning

confidence: 99%

Section: Structural and Biochemical Properties Of A-synmentioning

confidence: 99%

See 1 more Smart Citation

Role of post-translational modifications in modulating the structure, function and toxicity of α-synuclein

Oueslati

Fournier

Lashuel

2010

Progress in Brain Research

327

282

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“…7 The binding of copper to disease causing proteins, A-b peptide, a-synuclein, and prion proteins results in free radical production and associated oxidative stress (OS). 4,[7][8][9] Elevated copper levels play a primary role in Wilson's disease (hepatolenticular degeneration). Wilson's disease is an autosomal recessive inherited disorder, generally presenting toward the second decade of life.…”

mentioning

confidence: 99%

The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes

Reddy

Rao

Norenberg

2008

Laboratory Investigation

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Copper is an essential element and an integral component of various enzymes. However, excess copper is neurotoxic and has been implicated in the pathogenesis of Wilson's disease, Alzheimer's disease, prion conditions, and other disorders. Although mechanisms of copper neurotoxicity are not fully understood, copper is known to cause oxidative stress and mitochondrial dysfunction. As oxidative stress is an important factor in the induction of the mitochondrial permeability transition (mPT), we determined whether mPT plays a role in copper-induced neural cell injury. Cultured astrocytes and neurons were treated with 20 mM copper and mPT was measured by changes in the cyclosporin A (CsA)-sensitive inner mitochondrial membrane potential (DCm), employing the potentiometric dye TMRE. In astrocytes, copper caused a 36% decrease in the DCm at 12 h, which decreased further to 48% by 24 h and remained at that level for at least 72 h. Cobalt quenching of calcein fluorescence as a measure of mPT similarly displayed a 45% decrease at 24 h. Pretreatment with antioxidants significantly blocked the copper-induced mPT by 48-75%. Copper (24 h) also caused a 30% reduction in ATP in astrocytes, which was completely blocked by CsA. Copper caused death (42%) in astrocytes by 48 h, which was reduced by antioxidants (35-60%) and CsA (41%). In contrast to astrocytes, copper did not induce mPT in neurons. Instead, it caused early and extensive death with a concomitant reduction (63%) in ATP by 14 h. Neuronal death was prevented by antioxidants and nitric oxide synthase inhibitors but not by CsA. Copper increased protein tyrosine nitration in both astrocytes and neurons. These studies indicate that mPT, and oxidative and nitrosative stress represent major factors in copper-induced toxicity in astrocytes, whereas oxidative and nitrosative stress appears to play a major role in neuronal injury.

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“…Since the C-terminal region of α-Syn is involved in interaction with proteins [103,104,109] and metal ions [138][139][140], any phosphorylation in this site can alter its interaction capability [77]. The significance of α-Syn phosphorylation at serine129 has gained importance in PD because its accumulation is distinctly enhanced in the diseased condition.…”

Section: Resultsmentioning

confidence: 99%

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

Ganapathy¹

2017

Protein Phosphorylation

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Post-translational protein modifications play an important role in generating the large diversity of the proteome in comparison to the relatively small number of genes; phosphorylation being the most widespread. Phosphorylation of proteins regulates important molecularswitches for several cellular events and abnormal phosphorylation events are associated in many neurodegenerative diseases. In Parkinson's disease (PD) the main hallmark is the accumulation of cytoplasmic inclusions, Lewy bodies (LBs), consisting of α-synuclein (α-Syn) and ubiquitin. There's another key observation which is increasingly gaining prominence is a modified-form of α-Syn; the phospho α-Syn serine129 (pSyn). The significance of pSyn has gained importance in PD because its accumulation is distinctly enhanced in the diseased condition. The revelation of the involvement of pSyn on α-Syn aggregation, LB formation and neurotoxicity is crucial to understanding the pathogenesis and progression of PD. Since some in vitro and in vivo studies have indicated that pSyn is an early event preceding apoptosis, some important questions now needs to be explored in reference to the physiological functions regulated by phosphorylation, such as dopamine synthesis, vesicle mobilization, regulation of synaptic proteins, and synaptic plasticity. An investigation of the role of enzymes on the phosphorylation and clearance of α-Syn and region-specific susceptibility is required to be determined; to identify viable targets for new therapeutics.

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Interactions between metals and α‐synuclein − function or artefact?

Cited by 54 publications

References 83 publications

Role of post-translational modifications in modulating the structure, function and toxicity of α-synuclein

Role of post-translational modifications in modulating the structure, function and toxicity of α-synuclein

The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

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