Phosphorylated <i>α</i>-Synuclein-Copper Complex Formation in the Pathogenesis of Parkinson’s Disease

Castillo-Gonzalez, Juan Antonio; Loera-Arias, Maria De Jesus; Saucedo-Cardenas, Odila; Montes-de-Oca-Luna, Roberto; Garcia-Garcia, Aracely; Rodriguez-Rocha, Humberto

doi:https://doi.org/10.1155/2017/9164754

Parkinson’s Disease

On this page

Abstract Introduction Conflicts of Interest Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2017 | Article ID 9164754 | https://doi.org/10.1155/2017/9164754

Phosphorylated α-Synuclein-Copper Complex Formation in the Pathogenesis of Parkinson’s Disease

Juan Antonio Castillo-Gonzalez,¹Maria De Jesus Loera-Arias,¹Odila Saucedo-Cardenas,^1,2Roberto Montes-de-Oca-Luna,¹Aracely Garcia-Garcia,¹and Humberto Rodriguez-Rocha¹

Academic Editor: Jan Aasly

Received23 Aug 2017

Accepted11 Oct 2017

Published23 Nov 2017

Abstract

Parkinson’s disease is the second most important neurodegenerative disorder worldwide. It is characterized by the presence of Lewy bodies, which are mainly composed of α-synuclein and ubiquitin-bound proteins. Both the ubiquitin proteasome system (UPS) and autophagy-lysosomal pathway (ALS) are altered in Parkinson’s disease, leading to aggregation of proteins, particularly α-synuclein. Interestingly, it has been observed that copper promotes the protein aggregation process. Additionally, phosphorylation of -synuclein along with copper also affects the protein aggregation process. The interrelation among α-synuclein phosphorylation and its capability to interact with copper, with the subsequent disruption of the protein degradation systems in the neurodegenerative process of Parkinson’s disease, will be analyzed in detail in this review.

1. Introduction

Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder related to aging worldwide [1]. The clinical symptoms of this disease are resting tremor, rigidity, bradykinesia, akinesia, postural instability, difficulty in speech, and breathing problems [2]. Most PD cases appear to be sporadic, and only about 5–10% of the cases are due to genetic mutations [3]. Exposure to environmental pollutants such as herbicides (paraquat), pesticides (rotenone), and toxic substances during the manufacture of narcotic drugs (MPTP⁺) and prolonged exposure to transition metals have been reported to be related to sporadic cases of PD [4–6]. PD is characterized by dopaminergic neuronal loss in the substantia nigra at the central nervous system (CNS), a significant reduction in dopamine levels, and the presence of Lewy bodies [7, 8]. Lewy bodies are composed of abnormal deposits of protein aggregates, particularly α-synuclein and ubiquitin-bound proteins [9]. Abnormal protein aggregation results from the UPS and ALS alteration, and the latter includes disruption of lysosomal hydrolase trafficking [10–12]. Interestingly, some metal ions such as copper have shown to promote the protein aggregation process [13–15]. Additionally, phosphorylation of α-synuclein, along with copper, accelerates the protein aggregation process [16, 17].

Therefore, in order to have a better understanding of the mechanisms involved in the neurodegenerative process of PD, the interrelation among α-synuclein phosphorylation and its capability to interact with copper, as well as the consequent disruption of the protein degradation systems, will be analyzed in detail in this review.

2. α-Synuclein

The main histological hallmark of PD is the presence of eosinophilic cytoplasmic inclusions known as Lewy bodies, which are localized in the substantia nigra and are formed mostly by α-synuclein [18–20]. α-Synuclein is a thermostable, preserved, and unfolded cytosolic protein [21], belonging to a family of homologous proteins called synucleins, and is expressed in approximately 80% of the total area of the human brain [22, 23]. α-Synuclein consists of 140 amino acid residues [24] organized in three structural regions: an amphipathic amino-terminal domain from 1 to 60 amino acid residues, responsible for the binding of α-synuclein to lipid vesicles [25, 26]; the NAC (non-amyloid-β component) region from 61 to 95 amino acid residues, also found in amyloid plaques of patients suffering from Alzheimer’s disease [27] and responsible for α-synuclein aggregation and β sheets arrangement [28]; and the carboxy-terminal domain from 96 to 140 amino acid residues, which is the main target for the protein phosphorylation [29, 30] (Figure 1(a)). α-Synuclein is primarily expressed in neurons at cytosolic level and is abundant in presynaptic terminals [31]. However, it has also been linked to synaptic vesicles, plasma membrane lipid rafts and the nucleus [32]. Up to date, the main normal function of α-synuclein has not been well defined. α-Synuclein has been related to different functions, including inhibition of tyrosine hydroxylase [33], inhibition of dopamine release [34], dopamine uptake [35], neural plasticity, synaptic maturation and maintenance [36–38], and v-SNARE complex assembly [39, 40].

(a)

(b)

Figure 1

Schematic structure of -synuclein. (a) α-Synuclein mutations related to familial PD are shown as red squares. Metal-binding sites are depicted as yellow squares. Seine (S) and threonine (Y) amino acid residues targeted by phosphorylation are indicated as blue squares. (b) Amino acid composition of α-synuclein. Residues in blue represent copper-binding sites. Red squares indicate methionine 1 and histidine 50, which are independent anchoring sites for copper binding. Green squares show phosphorylation sites (Y125 and S129) related to an increased copper-binding capability.

α-Synuclein has the capability to assemble into amyloid fibers, soluble oligomers, and/or aggregates. Once the accumulation of α-synuclein surpasses its degradation rate, it leads to the formation of Lewy bodies and the subsequent death of dopaminergic neurons in the substantia nigra [41]. It has been suggested that α-synuclein protofibrils are responsible for the neurotoxic effects induced by α-synuclein [42, 43]. Among the possible mechanisms involved in the neurotoxicity mediated by α-synuclein are the following: mitochondrial dysfunction, oxidative stress [44], lysosomal leakage [45], cytoskeletal disruption [46], altered axonal transport, and subsequent synapses dysfunction, which are all related to neurodegeneration [47]. α-Synuclein is targeted for degradation by the UPS and the ALS including the chaperone-mediated autophagy (CMA) and macroautophagy (autophagy) [48–51]. Importantly, both degradation pathways are dysregulated or inhibited in PD [52].

The relationship between α-synuclein and PD was established with the identification of specific mutations in the SNCA gene encoding for α-synuclein, in families with PD. The specific mutations identified in α-synuclein were a substitution from alanine to threonine at amino acid residue 53 (A53T), a mutation of Greek origin [53]; a substitution from alanine to proline at amino acid residue 30 (A30P), a mutation of Germanic origin [54]; and a substitution from glutamic acid to lysine at amino acid residue 46 (E46K), a mutation of Spanish origin [55] (Figure 1(a)). Recently, two new mutations have been identified, a substitution from histidine to glutamine at amino acid residue 50 (H50Q) [56] and a substitution from glycine to aspartic acid at amino acid residue 51 (G51D), a mutation of French origin [57]. Additionally, SNCA gene duplication [58] and triplication also occur and are related to PD [59].

3. α-Synuclein Phosphorylation in Parkinson’s Disease: Neuroprotective or Neurotoxic?

In the aggregation process of α-synuclein, its phosphorylation plays an important role [29, 60] by directing its localization and interaction [61] and by modifying its secondary and tertiary conformation [62–65]. α-Synuclein is targeted by phosphorylation on multiple sites located at its carboxy-terminal end (S87, S129, Y125, Y133, and Y136) [66–71] (Figure 1). Several kinases have been linked to α-synuclein phosphorylation, such as casein kinases 1 and 2 (CK1 and CK2), G protein-coupled receptor kinases 2 and 5 (GRK2 and GRK5), polo-like kinase 2 (PLK2) [29, 72, 73], Fyn [74], and more recently serine/threonine protein kinase (LK6) and MAP kinase-interacting kinase 2a (Mnk2a) [75].

Studies performed in cell cultures with neuronal phenotype have demonstrated that CK2-mediated α-synuclein phosphorylation, particularly at S129, increases the appearance of eosinophilic cytoplasmic inclusions resembling the Lewy bodies of PD [76]. A major component of these inclusions consists of C-terminally truncated α-synuclein, and lysosomal proteases, such as cathepsin D, may be involved in its production for α-synuclein oligomerization [77]. Some mechanisms are triggered by the phosphorylation of α-synuclein, including the unfolded protein response (UPR) and disruption of lysosomal degradation pathways, which may lead to protein aggregation and subsequently to cell death (Figure 2) [78, 79]. Monomers and dimers of α-synuclein are degraded by ALS, specifically, CMA [79, 80]. In addition, it has been reported that a phosphorylated-like mutant version of α-synuclein (S129E), which mimics the biochemical and biophysical properties of α-syn phosphorylation observed in PD patients’ brains [76] and remained “phosphorylated-like” after exposure to the lysosomal fraction, cannot translocate across the lysosomal membrane probably because of a conformational change induced by its phosphorylation, decreasing its interaction with the CMA receptor (LAMP-2A) at the lysosomal membrane [79, 80].

Figure 2

Cell alterations involved in the aggregation process of -synuclein. Damaged or unrequired proteins are regulated by both the proteasomal and lysosomal degradation pathways. UPS disruption leads to activation of the ALS and vice versa, as a compensation mechanism. Both mechanisms are affected in PD, which results in protein accumulation including α-synuclein and ubiquitin-bound proteins. Accumulation of unfolded or misfolded proteins into the endoplasmic reticulum activates the unfolded protein response. Mitochondrial dysfunction and oxidative stress are also interrelated and linked to the pathogenesis of PD. All these alterations are associated with the phosphorylation process of α-synuclein and increase α-synuclein oligomerization, leading to Lewy body formation and subsequent apoptotic cell death.

In addition, dysfunctional mitochondrial metabolism and increased ROS production are also related to the phosphorylation of α-synuclein (Figure 3) [81]. Hydrogen peroxide- (H₂O₂-) induced oxidative stress increases the phosphorylation of α-synuclein at S129 and the formation of cytoplasmic inclusions [76]. On the other hand, some neurotoxins and the UPS inhibition increase the activity of GRK5 and CK2, whose interaction with Ca²⁺/calmodulin increases α-synuclein phosphorylation at S129 [82–84]. Rotenone, an inhibitor of mitochondrial complex I, along with iron, increases the levels of α-synuclein phosphorylation at S129, by inducing ROS production in dopaminergic cells [81].

Figure 3

-Synuclein-copper complex formation process. Copper can be found in living organisms in both forms, oxidized Cu²⁺ and reduced Cu⁺, and enters into the cell as Cu⁺ through CTR1 and CTR2. Afterwards, copper is transported to the nuclei, endoplasmic reticulum, and mitochondria via chaperone proteins. An overload of copper may lead to the α-synuclein-copper complex formation by three potential mechanisms. In the first one, a single α-synuclein molecule binds to Cu²⁺, folding and bringing together the amino and carboxy-terminal ends. The second mechanism involves two molecules of α-synuclein with a head-to-tail arrangement, generating a copper-binding site at both ends. In the third mechanism, the carboxy-terminal region of one molecule of α-synuclein interacts with the amino-terminal region from another molecule of α-synuclein creating a Cu²⁺ binding site. Next, one of the two α-synucleins interacts with a third α-synuclein molecule, forming a second Cu²⁺ binding site. This process will eventually lead to α-synuclein oligomerization.

So far, the role of α-synuclein phosphorylation is controversial. Some studies have shown a neuroprotective role of α-synuclein phosphorylation at S129 by preventing the binding of α-synuclein oligomers to membranes and, therefore, cellular disruption [85–88]. Additionally, phosphorylation at S129 blocked α-synuclein fibrillation in vitro [89]. Many studies had focused on the role of α-synuclein phosphorylation, specifically at S129, and also at other residues such as S87. α-Synuclein mutant variants, capable of mimicking or inhibiting the phosphorylation process (S129D, S129E, and S129A), have contributed to the elucidation of its role [66, 70, 89–92]. Phosphomimic mutants S129D/E were not able to reproduce in vitro the structural and aggregation properties of α-synuclein. However, a nonphosphomimic mutant S129A showed a higher protein aggregation rate and neurotoxicity than the wild type form [70, 71, 89].

On the contrary, there is evidence showing that α-synuclein phosphorylation at S129 induces cytotoxicity [66, 77, 93, 94]. It has been demonstrated that α-synuclein phosphorylation at S129 mediated by CK2 is an important factor for its protein aggregation and toxicity, inducing UPR dysregulation, endoplasmic reticulum (ER) stress, and apoptosis [78]. Besides, phosphorylation at S129 is essential for interaction of α-synuclein with synphilin-1 and parkin, which form the ubiquitinated inclusions [76]. Recently, it has been reported that α-synuclein can also be phosphorylated by LK6 and Mnk2a, with subsequent dopaminergic neuronal death and formation of cytoplasmic inclusions, respectively [75]. Nonetheless, it has been suggested that malfunction of the UPS increases CK2 activity, resulting in hyperphosphorylation of the α-synuclein at S129 [95].

Approximately 90% of α-synuclein detected in Lewy bodies from postmortem PD samples is phosphorylated at S129. Conversely, only 4% of α-synuclein present in normal brains is phosphorylated [66, 70, 96, 97]. Importantly, a mass spectrometry study in human cerebrospinal fluid (CSF) of PD and other parkinsonian disorders determined a significantly higher concentration of phosphorylated α-synuclein at S129, as well as a significant increase in the ratio of phosphorylated α-synuclein at S129/total α-synuclein in PD compared to healthy controls [98]. More recently, a marked difference between PD patients and healthy controls was observed with a sensitive and specific Elisa test, by combining measurements of total, oligomeric, and phosphorylated (S129) α-synuclein in CSF [99].

4. Interaction of Phosphorylated α-Synuclein with Metal Ions

Proteins are the main biomolecules affected in most pathologies; posttranslational modifications of proteins suchlike oxidation, nitration, carbonylation, glutathionylation, and phosphorylation are related to protein inactivation. Phosphorylated proteins have a strong binding affinity to certain metals [16, 100, 101]. Multivalent metal ions, like manganese, cobalt, iron, and mainly aluminum and copper, increase α-synuclein fibril formation by inducing conformational changes [14, 102, 103]. α-Synuclein may interact with different metal ions at either its carboxy-terminal domain or its amino-terminal domain, depending on the metal ion concentration [13]. For instance, at low concentrations (40–100 μM) Cu²⁺ ion binds to the amino-terminal domain [13, 104], while at extremely high concentrations (0.5–5 mM), which are unlikely to occur in tissues, metal ions such as Fe²⁺, Mn²⁺, Ni²⁺, Co²⁺, and Cu²⁺ bind to the carboxy-terminal domain [105]. Cu²⁺ ion is a potent inducer and accelerator of α-synuclein aggregation, linked to the carboxy-terminal domain, which is required for its oligomerization [106]. Phosphorylation at both Y125 and S129 residues of α-synuclein, which are close to metal-binding sites, increments Cu²⁺, Pb²⁺, and Fe²⁺ binding capability to carboxy-terminal domain (Figure 1) [17, 105].

5. Copper Mediates α-Synuclein Aggregation

On the other hand, copper has the ability to inhibit the proteasomal chymotrypsin-like peptidase activity [107]. Copper enters into the cell through the copper transporters 1 and 2 (CTR1 and CTR2), which are located on the cell membrane (Figure 3) [108]. Two regions, ¹MDVFMKGLS⁹ and ⁴⁸VVHGV⁵² (Figure 1), with high-affinity binding sites for copper were identified at α-synuclein, and may be of great biological importance in the pathogenesis of PD [104]. Within the α-synuclein sequence, methionine 1 and histidine 50 residues function as independent anchoring sites for copper binding (Figure 1) [104, 109, 110].

There are three models that have been suggested for copper binding to α-synuclein (Figure 3). In the first model, a single α-synuclein molecule binds to Cu²⁺, folding and bringing together the amino and carboxy-terminal regions. The second model involves two molecules of α-synuclein with a head-to-tail arrangement, generating a copper-binding site at both ends. In the third model, α-synuclein oligomerization takes place by interaction of the carboxy-terminal region of one molecule of α-synuclein with the amino-terminal region from a second molecule of α-synuclein originating a Cu²⁺ binding site; then a second Cu²⁺ binding site is formed by interaction of one of the two α-synucleins with a third α-synuclein molecule [15].

Regarding the aggregation process of α-synuclein mediated by copper, two mechanisms have been proposed. In one of them, high levels of α-synuclein-copper complexes will cause instability of intramolecular interactions leading to self-assembling of α-synuclein into fibrillar complexes. In the second one, copper redox-mediated reactions induce oxidation of α-synuclein using electron donors (NADH, NADPH, glutathione, etc.), causing its oligomerization and precipitation [111–114].

Environmental exposure to metal ions (e.g., zinc and copper) induces α-synuclein aggregates and oxidative stress, which are also associated with dysregulation of the UPS in PD [82, 115, 116].

Copper plays a dual role in the neurotoxic effect of α-synuclein. Once intracellular copper concentration is raised, chaperone proteins (e.g., ATOX1, CCS, MT3, and COX 17) are in charge to uptake this metal inside the cell, but an overload of copper might surpass the chaperone proteins available to regulate its levels. On the other hand, mutations affecting the ability of chaperones to bind copper might also increase its toxic effect [117]. Subsequently, free copper binds to the UPS to inhibit its activity; then α-synuclein is phosphorylated increasing its affinity to metals [71]. α-Synuclein-copper complex formation alters cell redox signaling, which results in ROS formation including H₂O₂. H₂O₂ oxidizes dopamine, which is toxic to dopaminergic neurons [118, 119].

6. Concluding Remarks

α-Synuclein is a highly relevant protein in PD etiopathology, and since the elucidation of α-synuclein-copper interactions, this transition metal was brought into the spotlight of neurodegeneration research. Although this complex formation is now subject of intense research, many open questions remain: How are levels of copper regulated by α-synuclein? Does copper influence α-synuclein phosphorylation and aggregation? How important is copper and α-synuclein interaction? Can we use phosphorylation of α-synuclein as a biomarker? Can we exploit the inhibition of phosphorylation of α-synuclein as a therapeutic approach? It is certain, that these therapies need to initiate promptly in order to address pathological changes in a less advanced stage. Regrettably, the diagnosis of PD nowadays is based on purely clinical signs, and these signs are manifested when more than half of dopaminergic neurons have died. Therefore, identification of early biomarkers such as α-synuclein phosphorylation may be a promising approach for diagnosis and subsequently for PD treatment and correlated with preclinical signs indicating incipient disease at a nonsymptomatic stage. Since α-synuclein and copper play such important roles in the aggregation process, a chelator administration is currently under investigation and may be a helpful approach against PD.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Acknowledgments

This work was supported by the National Council of Science and Technology (CONACYT) CB-2013-221615 (Aracely Garcia-Garcia) and Program for the Professional Development of the Professors (PRODEP) DSA/103.5/14/11175 (Humberto Rodriguez-Rocha). Juan Antonio Castillo-Gonzalez received a scholarship from CONACYT.

References

K. Wirdefeldt, H. Adami, P. Cole, D. Trichopoulos, and J. Mandel, “Epidemiology and etiology of Parkinson's disease: a review of the evidence,” European Journal of Epidemiology, vol. 26, supplement 1, pp. S1–S58, 2011.
View at: Publisher Site | Google Scholar
L. S. Forno, “Neuropathology of Parkinson's disease,” Journal of Neuropathology & Experimental Neurology, vol. 55, no. 3, pp. 259–272, 1996.
View at: Publisher Site | Google Scholar
S. Lesage and A. Brice, “Parkinson's disease: from monogenic forms to genetic susceptibility factors,” Human Molecular Genetics, vol. 18, no. R1, pp. R48–R59, 2009.
View at: Publisher Site | Google Scholar
B. C. L. Lai, S. A. Marion, K. Teschke, and J. K. C. Tsui, “Occupational and environmental risk factors for Parkinson's disease,” Parkinsonism & Related Disorders, vol. 8, no. 5, pp. 297–309, 2002.
View at: Publisher Site | Google Scholar
J. Peng, L. Peng, F. F. Stevenson, S. R. Doctrow, and J. K. Andersen, “Iron and paraquat as synergistic environmental risk factors in sporadic Parkinson's disease accelerate age-related neurodegeneration,” The Journal of Neuroscience, vol. 27, no. 26, pp. 6914–6922, 2007.
View at: Publisher Site | Google Scholar
K. Opeskin and R. M. Anderson, “Suspected MPTP-induced parkinsonism,” Journal of Clinical Neuroscience, vol. 4, no. 3, pp. 366–370, 1997.
View at: Publisher Site | Google Scholar
C. W. Shults, “Lewy bodies,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 103, no. 6, pp. 1661–1668, 2006.
View at: Publisher Site | Google Scholar
O. Hornykiewicz, “The discovery of dopamine deficiency in the parkinsonian brain,” Journal of Neural Transmission. Supplementa, vol. 70, pp. 9–15, 2006.
View at: Google Scholar
M. S. Pollanen, D. W. Dickson, and C. Bergeron, “Pathology and biology of the lewy body,” Journal of Neuropathology & Experimental Neurology, vol. 52, no. 3, pp. 183–191, 1993.
View at: Publisher Site | Google Scholar
C. Cook, C. Stetler, and L. Petrucelli, “Disruption of protein quality control in Parkinson's disease,” Cold Spring Harbor Perspectives in Medicine, vol. 2, no. 5, Article ID a009423, 2012.
View at: Publisher Site | Google Scholar
D. Ebrahimi-Fakhari, L. Wahlster, and P. J. McLean, “Protein degradation pathways in Parkinson's disease: curse or blessing,” Acta Neuropathologica, vol. 124, no. 2, pp. 153–172, 2012.
View at: Publisher Site | Google Scholar
J. R. Mazzulli, F. Zunke, O. Isacson, L. Studer, and D. Krainc, “α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 113, no. 7, pp. 1931–1936, 2016.
View at: Publisher Site | Google Scholar
A. Binolfi, R. M. Rasia, C. W. Bertoncini et al., “Interaction of α-synuclein with divalent metal ions reveals key differences: a link between structure, binding specificity and fibrillation enhancement,” Journal of the American Chemical Society, vol. 128, no. 30, pp. 9893–9901, 2006.
View at: Publisher Site | Google Scholar
L. Breydo and V. N. Uversky, “Role of metal ions in aggregation of intrinsically disordered proteins in neurodegenerative diseases,” Metallomics, vol. 3, no. 11, pp. 1163–1180, 2011.
View at: Publisher Site | Google Scholar
D. R. Brown, “Metal binding to alpha-synuclein peptides and its contribution to toxicity,” Biochemical and Biophysical Research Communications, vol. 380, no. 2, pp. 377–381, 2009.
View at: Publisher Site | Google Scholar
L. L. Liu and K. J. Franz, “Phosphorylation-dependent metal binding by α-synuclein peptide fragments,” Journal of Biological Inorganic Chemistry, vol. 12, no. 2, pp. 234–247, 2007.
View at: Publisher Site | Google Scholar
Y. Lu, M. Prudent, B. Fauvet, H. A. Lashuel, and H. H. Girault, “Phosphorylation of α-synuclein at Y125 and S129 alters its metal binding properties: implications for understanding the role of α-synuclein in the pathogenesis of Parkinson's disease and related disorders,” ACS Chemical Neuroscience, vol. 2, no. 11, pp. 667–675, 2011.
View at: Publisher Site | Google Scholar
A. J. Hughes, S. E. Daniel, Y. Ben-Shlomo, and A. J. Lees, “The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service,” Brain, vol. 125, no. 4, pp. 861–870, 2002.
View at: Publisher Site | Google Scholar
P. T. Kotzbauer, J. Q. Trojanowski, and V. M.-Y. Lee, “Lewy body pathology in Alzheimer's disease,” Journal of Molecular Neuroscience, vol. 17, no. 2, pp. 225–232, 2001.
View at: Publisher Site | Google Scholar
M. G. Spillantini, M. L. Schmidt, V. M. Lee, J. Q. Trojanowski, R. Jakes, and M. Goedert, “α-synuclein in Lewy bodies,” Nature, vol. 388, no. 6645, pp. 839-840, 1997.
View at: Publisher Site | Google Scholar
M. Goedert, “Alpha-synuclein and neurodegenerative diseases,” Nature Reviews Neuroscience, vol. 2, no. 7, pp. 492–501, 2001.
View at: Publisher Site | Google Scholar
E. Rockenstein, L. A. Hansen, M. Mallory, J. Q. Trojanowski, D. Galasko, and E. Masliah, “Altered expression of the synuclein family mRNA in Lewy body and Alzheimer's disease,” Brain Research, vol. 914, no. 1-2, pp. 48–56, 2001.
View at: Publisher Site | Google Scholar
R. Jakes, M. G. Spillantini, and M. Goedert, “Identification of two distinct synucleins from human brain,” FEBS Letters, vol. 345, no. 1, pp. 27–32, 1994.
View at: Publisher Site | Google Scholar
E. H. Norris, B. I. Giasson, and V. M.-Y. Lee, “α-Synuclein: Normal Function and Role in Neurodegenerative Diseases,” Current Topics in Developmental Biology, vol. 60, pp. 17–54, 2004.
View at: Publisher Site | Google Scholar
J. P. Segrest, M. K. Jones, H. De Loof, C. G. Brouillette, Y. V. Venkatachalapathi, and G. M. Anantharamaiah, “The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function,” Journal of Lipid Research, vol. 33, no. 2, pp. 141–166, 1992.
View at: Google Scholar
W. S. Davidson, A. Jonas, D. F. Clayton, and J. M. George, “Stabilization of α-synuclein secondary structure upon binding to synthetic membranes,” The Journal of Biological Chemistry, vol. 273, no. 16, pp. 9443–9449, 1998.
View at: Publisher Site | Google Scholar
K. Ueda, H. Fukushima, E. Masliah et al., “Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 90, no. 23, pp. 11282–11286, 1993.
View at: Publisher Site | Google Scholar
A. M. Bodles, D. J. S. Guthrie, B. Greer, and G. Brent Irvine, “Identification of the region of non-Aβ component (NAC) of Alzheimer's disease amyloid responsible for its aggregation and toxicity,” Journal of Neurochemistry, vol. 78, no. 2, pp. 384–395, 2001.
View at: Publisher Site | Google Scholar
M. Okochi, J. Walter, A. Koyama et al., “Constitutive phosphorylation of the Parkinson's disease associated α- synuclein,” The Journal of Biological Chemistry, vol. 275, no. 1, pp. 390–397, 2000.
View at: Publisher Site | Google Scholar
M. P. Sang, Y. J. Han, T. D. Kim, H. P. Jeon, C.-H. Yang, and J. Kim, “Distinct roles of the N-terminal-binding domain and the C-terminal-solubilizing domain of α-synuclein, a molecular chaperone,” The Journal of Biological Chemistry, vol. 277, no. 32, pp. 28512–28520, 2002.
View at: Publisher Site | Google Scholar
D. F. Clayton and J. M. George, “The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease,” Trends in Neurosciences, vol. 21, no. 6, pp. 249–254, 1998.
View at: Publisher Site | Google Scholar
M. C. Bennett, “The role of α-synuclein in neurodegenerative diseases,” Pharmacology & Therapeutics, vol. 105, no. 3, pp. 311–331, 2005.
View at: Publisher Site | Google Scholar
R. G. Perez, J. C. Waymire, E. Lin, J. J. Liu, F. Guo, and M. J. Zigmond, “A role for alpha-synuclein in the regulation of dopamine biosynthesis,” The Journal of Neuroscience, vol. 22, pp. 3090–3099, 2002.
View at: Google Scholar
K. E. Larsen, Y. Schmitz, M. D. Troyer et al., “α-Synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis,” The Journal of Neuroscience, vol. 26, no. 46, pp. 11915–11922, 2006.
View at: Publisher Site | Google Scholar
C. Wersinger and A. Sidhu, “Disruption of the interaction of α-synuclein with microtubules enhances cell surface recruitment of the dopamine transporter,” Biochemistry, vol. 44, no. 41, pp. 13612–13624, 2005.
View at: Publisher Site | Google Scholar
D. E. Cabin, K. Shimazu, D. Murphy et al., “Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking α-synuclein,” The Journal of Neuroscience, vol. 22, no. 20, pp. 8797–8807, 2002.
View at: Google Scholar
W. Dauer, N. Kholodilov, M. Vila et al., “Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 99, no. 22, pp. 14524–14529, 2002.
View at: Publisher Site | Google Scholar
A. Abeliovich, Y. Schmitz, I. Fariñas et al., “Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system,” Neuron, vol. 25, no. 1, pp. 239–252, 2000.
View at: Publisher Site | Google Scholar
N. M. Bonini and B. I. Giasson, “Snaring the function of α-synuclein,” Cell, vol. 123, no. 3, pp. 359–361, 2005.
View at: Publisher Site | Google Scholar
J. Burré, M. Sharma, T. Tsetsenis, V. Buchman, M. R. Etherton, and T. C. Südhof, “α-Synuclein promotes SNARE-complex assembly in vivo and in vitro,” Science, vol. 329, no. 5999, pp. 1663–1667, 2010.
View at: Publisher Site | Google Scholar
J. E. Duda, V. M.-Y. Lee, and J. Q. Trojanowski, “Neuropathology of synuclein aggregates: New insights into mechanisms of neurodegenerative diseases,” Journal of Neuroscience Research, vol. 61, no. 2, pp. 121–127, 2000.
View at: Publisher Site | Google Scholar
R. A. Fredenburg, C. Rospigliosi, R. K. Meray et al., “The impact of the E46K mutation on the properties of α-synuclein in its monomelic and oligomeric states,” Biochemistry, vol. 46, no. 24, pp. 7107–7118, 2007.
View at: Publisher Site | Google Scholar
M. Periquet, T. Fulga, L. Myllykangas, M. G. Schlossmacher, and M. B. Feany, “Aggregated α-synuclein mediates dopaminergic neurotoxicity in vivo,” The Journal of Neuroscience, vol. 27, no. 12, pp. 3338–3346, 2007.
View at: Publisher Site | Google Scholar
L. J. Hsu, Y. Sagara, A. Arroyo et al., “alpha-synuclein promotes mitochondrial deficit and oxidative stress,” The American Journal of Pathology, vol. 157, no. 2, pp. 401–410, 2000.
View at: Publisher Site | Google Scholar
M. Hashimoto, K. Kawahara, P. Bar-On, E. Rockenstein, L. Crews, and E. Masliah, “The role of α-synuclein assembly and metabolism in the pathogenesis of Lewy body disease,” Journal of Molecular Neuroscience, vol. 24, no. 3, pp. 343–352, 2004.
View at: Publisher Site | Google Scholar
M. A. Alim, Q.-L. Ma, K. Takeda et al., “Demonstration of a role for α-synuclein as a functional microtubule-associated protein,” Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 435–442, 2004.
View at: Publisher Site | Google Scholar
D. A. Scott, I. Tabarean, Y. Tang, A. Cartier, E. Masliah, and S. Roy, “A pathologic cascade leading to synaptic dysfunction in α-synuclein-induced neurodegeneration,” The Journal of Neuroscience, vol. 30, no. 24, pp. 8083–8095, 2010.
View at: Publisher Site | Google Scholar
F. Yang, Y.-P. Yang, C.-J. Mao et al., “Crosstalk between the proteasome system and autophagy in the clearance of α-synuclein,” Acta Pharmacologica Sinica, vol. 34, no. 5, pp. 674–680, 2013.
View at: Publisher Site | Google Scholar
Y. Machiya, S. Hara, S. Arawaka et al., “Phosphorylated α-Synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin-independent manner,” The Journal of Biological Chemistry, vol. 285, no. 52, pp. 40732–40744, 2010.
View at: Publisher Site | Google Scholar
T. Vogiatzi, M. Xilouri, K. Vekrellis, and L. Stefanis, “Wild type α-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells,” The Journal of Biological Chemistry, vol. 283, no. 35, pp. 23542–23556, 2008.
View at: Publisher Site | Google Scholar
A. M. Cuervo, L. Stafanis, R. Fredenburg, P. T. Lansbury, and D. Sulzer, “Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy,” Science, vol. 305, no. 5688, pp. 1292–1295, 2004.
View at: Publisher Site | Google Scholar
J. L. Webb, B. Ravikumar, J. Atkins, J. N. Skepper, and D. C. Rubinsztein, “α-Synuclein is degraded by both autophagy and the proteasome,” The Journal of Biological Chemistry, vol. 278, no. 27, pp. 25009–25013, 2003.
View at: Publisher Site | Google Scholar
M. H. Polymeropoulos, C. Lavedan, E. Leroy et al., “Mutation in the α-synuclein gene identified in families with Parkinson's disease,” Science, vol. 276, no. 5321, pp. 2045–2047, 1997.
View at: Publisher Site | Google Scholar
R. Krüger, W. Kuhn, T. Müller et al., “Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease,” Nature Genetics, vol. 18, no. 2, pp. 106–108, 1998.
View at: Publisher Site | Google Scholar
J. J. Zarranz, J. Alegre, J. C. Gómez-Esteban et al., “The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia,” Annals of Neurology, vol. 55, no. 2, pp. 164–173, 2004.
View at: Publisher Site | Google Scholar
S. Appel-Cresswell, C. Vilarino-Guell, M. Encarnacion et al., “Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease,” Movement Disorders, vol. 28, no. 6, pp. 811–813, 2013.
View at: Publisher Site | Google Scholar
S. Lesage, M. Anheim, F. Letournel et al., “G51D α-synuclein mutation causes a novel Parkinsonian-pyramidal syndrome,” Annals of Neurology, vol. 73, no. 4, pp. 459–471, 2013.
View at: Publisher Site | Google Scholar
M. Chartier-Harlin, J. Kachergus, C. Roumier et al., “α-synuclein locus duplication as a cause of familial Parkinson's disease,” The Lancet, vol. 364, no. 9440, pp. 1167–1169, 2004.
View at: Publisher Site | Google Scholar
A. B. Singleton, M. Farrer, J. Johnson et al., “α-synuclein locus triplication causes Parkinson's disease,” Science, vol. 302, no. 5646, article 841, 2003.
View at: Publisher Site | Google Scholar
J. P. Anderson, D. E. Walker, J. M. Goldstein et al., “Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic lewy body disease,” The Journal of Biological Chemistry, vol. 281, no. 40, pp. 29739–29752, 2006.
View at: Publisher Site | Google Scholar
T. Hunter, “Signaling—2000 and beyond,” Cell, vol. 100, no. 1, pp. 113–127, 2000.
View at: Publisher Site | Google Scholar
A. A. Bielska and N. J. Zondlo, “Hyperphosphorylation of tau induces local polyproline II helix,” Biochemistry, vol. 45, no. 17, pp. 5527–5537, 2006.
View at: Publisher Site | Google Scholar
N. Errington and A. J. Doig, “A phosphoserine-lysine salt bridge within an α-helical peptide, the strongest α-helix side-chain interaction measured to date,” Biochemistry, vol. 44, no. 20, pp. 7553–7558, 2005.
View at: Publisher Site | Google Scholar
R. S. Signarvic and W. F. DeGrado, “De novo design of a molecular switch: Phosphorylation-dependent association of designed peptides,” Journal of Molecular Biology, vol. 334, no. 1, pp. 1–12, 2003.
View at: Publisher Site | Google Scholar
A. Tholey, A. Lindemann, V. Kinzel, and J. Reed, “Direct effects of phosphorylation on the preferred backbone conformation of peptides: A nuclear magnetic resonance study,” Biophysical Journal, vol. 76, no. 1 I, pp. 76–87, 1999.
View at: Publisher Site | Google Scholar
L. Chen and M. B. Feany, “α-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease,” Nature Neuroscience, vol. 8, no. 5, pp. 657–663, 2005.
View at: Publisher Site | Google Scholar
B.-H. Ahn, H. Rhim, Y.-M. S. Shi Yeon Kim et al., “α-synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase d activation in human embryonic kidney-293 cells,” The Journal of Biological Chemistry, vol. 277, no. 14, pp. 12334–12342, 2002.
View at: Publisher Site | Google Scholar
T. Nakamura, H. Yamashita, T. Takahashi, and S. Nakamura, “Activated Fyn phosphorylates α-synuclein at tyrosine residue 125,” Biochemical and Biophysical Research Communications, vol. 280, no. 4, pp. 1085–1092, 2001.
View at: Publisher Site | Google Scholar
C. E. Ellis, P. L. Schwartzberg, T. L. Grider, D. W. Fink, and R. L. Nussbaum, “α-Synuclein Is Phosphorylated by Members of the Src Family of Protein-tyrosine Kinases,” The Journal of Biological Chemistry, vol. 276, no. 6, pp. 3879–3884, 2001.
View at: Publisher Site | Google Scholar
H. Sato, S. Arawaka, S. Hara et al., “Authentically phosphorylated α-synuclein at Ser129 accelerates neurodegeneration in a rat model of familial Parkinson's disease,” The Journal of Neuroscience, vol. 31, no. 46, pp. 16884–16894, 2011.
View at: Publisher Site | Google Scholar
H. Sato, T. Kato, and S. Arawaka, “The role of Ser129 phosphorylation of α-synuclein in neurodegeneration of Parkinson's disease: A review of in vivo models,” Reviews in the Neurosciences, vol. 24, no. 2, pp. 115–123, 2013.
View at: Google Scholar
K. J. Inglis, D. Chereau, E. F. Brigham et al., “Polo-like kinase 2 (PLK2) phosphorylates α-synuclein at serine 129 in central nervous system,” The Journal of Biological Chemistry, vol. 284, no. 5, pp. 2598–2602, 2009.
View at: Publisher Site | Google Scholar
A. N. Pronin, A. J. Morris, A. Surguchov, and J. L. Benovic, “Synucleins are a novel class of substrates for G protein-coupled receptor kinases,” The Journal of Biological Chemistry, vol. 275, no. 34, pp. 26515–26522, 2000.
View at: Publisher Site | Google Scholar
J. Kosten, A. Binolfi, M. Stuiver et al., “Efficient modification of alpha-synuclein serine 129 by protein kinase CK1 requires phosphorylation of tyrosine 125 as a priming event,” ACS Chemical Neuroscience, vol. 5, no. 12, pp. 1203–1208, 2014.
View at: Publisher Site | Google Scholar
S. Zhang, J. Xie, Y. Xia et al., “LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration,” Scientific Reports, vol. 5, Article ID 12564, 2015.
View at: Publisher Site | Google Scholar
W. W. Smith, R. L. Margolis, X. Li et al., “α-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells,” The Journal of Neuroscience, vol. 25, no. 23, pp. 5544–5552, 2005.
View at: Publisher Site | Google Scholar
M. Takahashi, L.-W. Ko, J. Kulathingal, P. Jiang, D. Sevlever, and S.-H. C. Yen, “Oxidative stress-induced phosphorylation, degradation and aggregation of α-synuclein are linked to upregulated CK2 and cathepsin D,” European Journal of Neuroscience, vol. 26, no. 4, pp. 863–874, 2007.
View at: Publisher Site | Google Scholar
N. Sugeno, A. Takeda, T. Hasegawa et al., “Serine 129 phosphorylation of α-synuclein induces unfolded protein response-mediated cell death,” The Journal of Biological Chemistry, vol. 283, no. 34, pp. 23179–23188, 2008.
View at: Publisher Site | Google Scholar
M. Martinez-Vicente, Z. Talloczy, S. Kaushik et al., “Dopamine-modified α-synuclein blocks chaperone-mediated autophagy,” The Journal of Clinical Investigation, vol. 118, no. 2, pp. 777-778, 2008.
View at: Publisher Site | Google Scholar
S. K. Mak, A. L. McCormack, A. B. Manning-Bog, A. M. Cuervo, and D. A. Di Monte, “Lysosomal degradation of α-synuclein in vivo,” The Journal of Biological Chemistry, vol. 285, no. 18, pp. 13621–13629, 2010.
View at: Publisher Site | Google Scholar
R. Perfeito, D. F. Lázaro, T. F. Outeiro, and A. C. Rego, “Linking alpha-synuclein phosphorylation to reactive oxygen species formation and mitochondrial dysfunction in SH-SY5Y cells,” Molecular and Cellular Neuroscience, vol. 62, pp. 51–59, 2014.
View at: Publisher Site | Google Scholar
K.-Y. Chau, H. L. Ching, A. H. V. Schapira, and J. M. Cooper, “Relationship between alpha synuclein phosphorylation, proteasomal inhibition and cell death: Relevance to Parkinson's disease pathogenesis,” Journal of Neurochemistry, vol. 110, no. 3, pp. 1005–1013, 2009.
View at: Publisher Site | Google Scholar
A. N. Pronin, C. V. Carman, and J. L. Benovic, “Structure-function analysis of G protein-coupled receptor kinase-5: Role of the carboxyl terminus in kinase regulation,” The Journal of Biological Chemistry, vol. 273, no. 47, pp. 31510–31518, 1998.
View at: Publisher Site | Google Scholar
T. T. Chuang, L. Paolucci, and A. De Blasi, “Inhibition of G protein-coupled receptor kinase subtypes by Ca2+/calmodulin,” The Journal of Biological Chemistry, vol. 271, no. 45, pp. 28691–28696, 1996.
View at: Publisher Site | Google Scholar
G. S. Nübling, J. Levin, B. Bader et al., “Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers,” PLoS ONE, vol. 9, no. 6, Article ID e98906, 2014.
View at: Publisher Site | Google Scholar
T. Kuwahara, R. Tonegawa, G. Ito, S. Mitani, and T. Iwatsubo, “Phosphorylation of α-synuclein protein at ser-129 reduces neuronal dysfunction by lowering its membrane binding property in Caenorhabditis elegans,” The Journal of Biological Chemistry, vol. 287, no. 10, pp. 7098–7109, 2012.
View at: Publisher Site | Google Scholar
V. Sancenon, S.-A. Lee, C. Patrick et al., “Suppression of α-synuclein toxicity and vesicle trafficking defects by phosphorylation at S129 in yeast depends on genetic context,” Human Molecular Genetics, vol. 21, no. 11, Article ID dds058, pp. 2432–2449, 2012.
View at: Publisher Site | Google Scholar
B. Wu, Q. Liu, C. Duan et al., “Phosphorylation of α-synuclein upregulates tyrosine hydroxylase activity in MN9D cells,” Acta Histochemica, vol. 113, no. 1, pp. 32–35, 2011.
View at: Publisher Site | Google Scholar
K. E. Paleologou, A. W. Schmid, C. C. Rospigliosi et al., “Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of α-synuclein,” The Journal of Biological Chemistry, vol. 283, no. 24, pp. 16895–16905, 2008.
View at: Publisher Site | Google Scholar
N. R. McFarland, Z. Fan, K. Xu et al., “α-Synuclein S129 phosphorylation mutants do not alter nigrostriatal toxicity in a rat model of parkinson disease,” Journal of Neuropathology & Experimental Neurology, vol. 68, no. 5, pp. 515–524, 2009.
View at: Publisher Site | Google Scholar
O. S. Gorbatyuk, S. Li, L. F. Sullivan et al., “The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 105, no. 2, pp. 763–768, 2008.
View at: Publisher Site | Google Scholar
K. E. Paleologou, A. Oueslati, G. Shakked et al., “Phosphorylation at S87 is enhanced in synucleinopathies, inhibits α-synuclein oligomerization, and influences synuclein-membrane interactions,” The Journal of Neuroscience, vol. 30, no. 9, pp. 3184–3198, 2010.
View at: Publisher Site | Google Scholar
M. Yamada, T. Iwatsubo, Y. Mizuno, and H. Mochizuki, “Overexpression of α-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of α-synuclein and activation of caspase-9: Resemblance to pathogenetic changes in Parkinson's disease,” Journal of Neurochemistry, vol. 91, no. 2, pp. 451–461, 2004.
View at: Publisher Site | Google Scholar
A. L. McCormack, S. K. Mak, and D. A. Di Monte, “Increased a-synuclein phosphorylation and nitration in the aging primate substantia nigra,” Cell Death & Disease, vol. 3, no. 5, article no. e315, 2012.
View at: Publisher Site | Google Scholar
E. A. Waxman and B. I. Giasson, “Specificity and regulation of casein kinase-mediated phosphorylation of α-synuclein,” Journal of Neuropathology & Experimental Neurology, vol. 67, no. 5, pp. 402–416, 2008.
View at: Publisher Site | Google Scholar
H. Fujiwara, M. Hasegawa, N. Dohmae et al., “α-synuclein is phosphorylated in synucleinopathy lesions,” Nature Cell Biology, vol. 4, no. 2, pp. 160–164, 2002.
View at: Publisher Site | Google Scholar
M. Hasegawa, H. Fujiwara, T. Nonaka et al., “Phosphorylated α-synuclein is ubiquitinated in α-synucleinopathy lesions,” The Journal of Biological Chemistry, vol. 277, no. 50, pp. 49071–49076, 2002.
View at: Publisher Site | Google Scholar
Y. Wang, M. Shi, and K. A. Chung, “Phosphorylated α-synuclein in Parkinson's disease,” Science Translational Medicine, vol. 4, no. 121, Article ID 121ra20, 2012.
View at: Publisher Site | Google Scholar
N. K. Majbour, N. N. Vaikath, K. D. Van Dijk et al., “Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease,” Molecular Neurodegeneration, vol. 11, no. 1, article no. 7, 2016.
View at: Publisher Site | Google Scholar
L. L. Liu and K. J. Franz, “Phosphorylation of an α-synuclein peptide fragment enhances metal binding,” Journal of the American Chemical Society, vol. 127, no. 27, pp. 9662-9663, 2005.
View at: Publisher Site | Google Scholar
A. Garcia-Garcia, H. Rodriguez-Rocha, N. Madayiputhiya, A. Pappa, M. I. Panayiotidis, and R. Franco, “Biomarkers of protein oxidation in human disease,” Current Molecular Medicine, vol. 12, no. 6, pp. 681–697, 2012.
View at: Publisher Site | Google Scholar
A. Santner and V. N. Uversky, “Metalloproteomics and metal toxicology of α-synuclein,” Metallomics, vol. 2, no. 6, pp. 378–392, 2010.
View at: Publisher Site | Google Scholar
V. N. Uversky, J. Li, and A. L. Fink, “Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein: A possible molecular link between parkinson's disease and heavy metal exposure,” The Journal of Biological Chemistry, vol. 276, no. 47, pp. 44284–44296, 2001.
View at: Publisher Site | Google Scholar
R. M. Rasia, C. W. Bertoncini, D. Marsh et al., “Structural characterization of copper(II) binding to α-synuclein: insights into the bioinorganic chemistry of Parkinson's disease,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 102, no. 12, pp. 4294–4299, 2005.
View at: Publisher Site | Google Scholar
A. Binolfi, L. Quintanar, C. W. Bertoncini, C. Griesinger, and C. O. Fernández, “Bioinorganic chemistry of copper coordination to alpha-synuclein: Relevance to Parkinson's disease,” Coordination Chemistry Reviews, vol. 256, no. 19-20, pp. 2188–2201, 2012.
View at: Publisher Site | Google Scholar
S. R. Paik, H.-J. Shin, J.-H. Lee, C.-S. Chang, and J. Kim, “Copper(II)-induced self-oligomerization of α-synuclein,” Biochemical Journal, vol. 340, no. 3, pp. 821–828, 1999.
View at: Publisher Site | Google Scholar
Y. Xiao, D. Chen, X. Zhang et al., “Molecular study on copper-mediated tumor proteasome inhibition and cell death,” International Journal of Oncology, vol. 37, pp. 81–87, 2010.
View at: Google Scholar
N. K. Y. Wee, D. C. Weinstein, S. T. Fraser, and S. J. Assinder, “The mammalian copper transporters CTR1 and CTR2 and their roles in development and disease,” The International Journal of Biochemistry & Cell Biology, vol. 45, no. 5, pp. 960–963, 2013.
View at: Publisher Site | Google Scholar
A. Binolfi, G. R. Lamberto, R. Duran et al., “Site-specific interactions of Cu(II) with α and β-synuclein: Bridging the molecular gap between metal binding and aggregation,” Journal of the American Chemical Society, vol. 130, no. 35, pp. 11801–11812, 2008.
View at: Publisher Site | Google Scholar
A. Binolfi, E. E. Rodriguez, D. Valensin et al., “Bioinorganic chemistry of Parkinson's disease: Structural determinants for the copper-mediated amyloid formation of alpha-synuclein,” Inorganic Chemistry, vol. 49, no. 22, pp. 10668–10679, 2010.
View at: Publisher Site | Google Scholar
H. R. Lucas and J. C. Lee, “Copper(ii) enhances membrane-bound α-synuclein helix formation,” Metallomics, vol. 3, no. 3, pp. 280–283, 2011.
View at: Publisher Site | Google Scholar
T. Kowalik-Jankowska, A. Rajewska, E. Jankowska, and Z. Grzonka, “Products of Cu(II)-catalyzed oxidation of α-synuclein fragments containing M1-D2 and H50 residues in the presence of hydrogen peroxide,” Dalton Transactions, no. 6, pp. 832–838, 2008.
View at: Publisher Site | Google Scholar
L. Guilloreau, S. Combalbert, M. Sournia-Saquet, H. Mazarguil, and P. Faller, “Redox chemistry of copper-amyloid-β: The generation of hydroxyl radical in the presence of ascorbate is linked to redox-potentials and aggregation state,” ChemBioChem, vol. 8, no. 11, pp. 1317–1325, 2007.
View at: Publisher Site | Google Scholar
T. Kowalik-Jankowska, A. Rajewska, E. Jankowska, and Z. Grzonka, “Copper(II) binding by fragments of α-synuclein containing M 1-D2- and -H50-residues; a combined potentiometric and spectroscopic study,” Dalton Transactions, no. 42, pp. 5068–5076, 2006.
View at: Publisher Site | Google Scholar
P. Jenner, “Oxidative stress in Parkinson’s disease,” Annals of Neurology, vol. 53, supplement 3, pp. S26–S38, 2003.
View at: Publisher Site | Google Scholar
H. Snyder, K. Mensah, C. Hsu et al., “β-Synuclein reduces proteasomal inhibition by α-synuclein but not γ-synuclein,” The Journal of Biological Chemistry, vol. 280, no. 9, pp. 7562–7569, 2005.
View at: Publisher Site | Google Scholar
S. Montes, S. Rivera-Mancia, A. Diaz-Ruiz, L. Tristan-Lopez, and C. Rios, “Copper and copper proteins in Parkinson's disease,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 147251, 2014.
View at: Publisher Site | Google Scholar
M. E. Rice and I. Russo-Menna, “Differential compartmentalization of brain ascorbate and glutathione between neurons and glia,” Neuroscience, vol. 82, no. 4, pp. 1213–1223, 1997.
View at: Publisher Site | Google Scholar
J. Sian, D. T. Dexter, A. J. Lees et al., “Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia,” Annals of Neurology, vol. 36, no. 3, pp. 348–355, 1994.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2017 Juan Antonio Castillo-Gonzalez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

2305

Downloads

1269

Citations