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 molecular-switches 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.
- phospho α-synuclein serine129
- Lewy bodies
Parkinson’s disease (PD) is the second most common diagnosed neurodegenerative disease  with a prevalence of about 1% at the age of 65 and of 4–5% by the age of 85 . The clinical manifestations of classical PD are rest tremor, rigidity, bradykinesia, and postural imbalance. The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) together with a distinct decrease in striatal dopamine, and the occurrence of cytoplasmic eosinophilic inclusions called Lewy bodies (LBs) are considered the pathological hallmarks of PD . There are also reports of other neuronal cell losses in locus coeruleus and olfactory lobe during the development of the disease . It has however been identified that the clinical manifestation of motor symptoms appears with the loss of DA neurons in the midbrain . According to Rodriguez-Oroz et al. , the anatomical-functional basis of the main clinical manifestations is related to the low level of dopamine concentration in contralateral striatum and the malfunction of dopamine circuits. Current medications for PD supplement dopamine (L-DOPA), or activate DA receptors (DA-receptor agonist), or inhibit the degradation of DA (monoamine oxidase B inhibitor and catechol-O-methyltransferase inhibitor), bringing about temporary abatement of motor symptoms but failing to delay or halt disease progression. The etiology of PD is still unknown: it comprises familial (fPD) forms accounting for less than 10% of all PD cases, and the far more common sporadic (sPD) form. The striking feature in both fPD and sPD is α-synuclein (α-Syn) aggregation with ubiquitin that eventually progresses to form LBs. Three missense mutations (A53T, A30P, and E46K) [7–9] of α-Syn are known to cause autosomal dominant fPD , probably through a gain-of-function mechanism. Moreover, overexpression of human α-Syn in mice results in progressive loss of DA terminals in the basal ganglia and accumulation of LB-like structures in neurons . Mechanisms that might control α-Syn aggregation in sPD are not clear, but may include transcription factor dysregulation  and the inability of normal degradation pathways to function adequately . El-Agnaf et al.  detected α-Syn species in live-human sPD and fPD patient plasma and cerebrospinal fluid.
2. α-Syn structure and function
Syn are a vertebrate-specific family of abundant neuronal proteins. They consist of three closely related members, α-,β-,and γ-Syn, of which α-Syn has been the prime focus ever since mutations in it were recognized as a basis for fPD. Syn is a highly conserved protein with a molecular weight of approximately 14 kDa, comprising 140 amino acids . This heat-resistant, soluble, acidic protein is abundant in the presynaptic terminals of central nervous system (CNS) neurons expressed pre-dominantly in the neocortex, hippocampus, SNpc, thalamus, and cerebellum [16–18]. Unlike α- and β-synuclein, γ-Syn is not concentrated in presynaptic terminals  and is largely found in the peripheral nervous system (PNS).
α-Syn is composed of three distinct domains: an N-terminal amphipathic repeat region that can form α-helices; a hydrophobic central segment; and a C-terminal acidic region (Figure 1).The highly conserved N-terminal domain (residues 1–65) includes 6 copies of an unusual 11 amino acid repeat that display variations of a KTKEGV consensus sequence. It is unordered in solution, but can shift to a α-helical conformation  comprising two distinct α-helices interrupted by a short break . α-Syn binds strongly to negatively charged phospholipids and becomes α-helical [22, 23], suggesting that the protein may normally be associated with the membrane . This N-terminal domain includes the three sites of the fPD mutations A30P, E46K, and A53T (Figure 1).
The hydrophobic central segment of α-Syn (non-amyloid component (NAC), residues 66–95) (Figure 1)  is the second major component of brain amyloid plaques in Alzheimer’s disease (AD) [18, 24]. This region consists of three repeats including the highly amyloidogenic part of the molecule that is responsible for α-Syn’s ability to undergo a conformational change from random coil to β-sheet structure  and to form Aβ-like protofibrils and fibrils [24, 25]. These properties differentiate α-Syn from β-Syn and γ-Syn, which fail to form co-polymers with α-Syn . The NAC region carries a phosphorylation site on Ser87 .
The acidic C-terminal domain (residues 96–140) of α-Syn has a strong negative charge composed primarily of acidic amino acids , but has no known structural elements. It consists of an acidic domain rich in proline residues (residues 125–140) that seems critical for the chaperone-like activity of α-Syn , as demonstrated by deletion mutants of the C-terminal region in which the α-Syn chaperone activity is lost [27–29]. In contrast to the amphipathic N-terminal and hydrophobic NAC regions, which are highly conserved between species, the C-terminal region is variable in size and in sequence [28–31]. This region is also organized in random structure in most conditions and contains several phosphorylation sites: Ser129, Tyr125, Tyr133, and Tyr136  (Figure 1).
Although the normal functions of α-Syn are still being defined, several studies have shown that this protein has a key role to play in membrane-associated processes at the presynaptic level such as formation and maintenance of synaptic vesicle pools (Figure 2), regulation of lipid metabolism, and Ca2+ homeostasis [31–33]. Greten-Harrison et al.  using αβγ-Syn knockout mice has reported that deletion of Syns causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival.
α-Syn also has been suggested to function as a chaperone protein
2.1. Phosphorylation of α-synuclein at serine129
Protein phosphorylation is a reversible post-translational modification of proteins that has an important role in regulating structural and functional properties of proteins in health and disease. It is primarily associated with signaling pathways and cellular processes in all aspects of cell biology such as cell-cycle progression, differentiation, apoptosis, metabolism, transcription, cytoskeletal arrangement, intercellular communication, motility and migration [42–44]. In eukaryotes, the amino acids that are most commonly reported to be phosphorylated are serine, threonine and tyrosine [45, 46] with few reports suggesting phosphorylation at arginine, lysine and cysteine residues [45, 47, 48].
In PD too, phosphorylation appears to play an important role in fibrillogenesis, LB formation, and neurotoxicity of α-Syn
2.2. Phosphorylation and CNS
The central processing unit of the human body is its CNS consisting of specialized cells called neurons relaying electrical and chemical signals to all parts of our body . However, the most abundant cell type in the CNS is the glial cells comprising of astrocytes, oligodendrocytes and microglia [59, 60]. In addition, it is interspersed with microvasculature that provides the nutrients and support to these CNS cells. The central theme in CNS function is equilibrium among these various cell types to maintain optimal synaptic strengths, neuronal firing rates, and neurotransmitter release. The regulation of these functions can be either through inside-out or outside-in stimuli and are strongly associated with several signaling pathways within these cells. Virtually every class of neuronal protein is regulated by phosphorylation and most types of extracellular signals, including neurotransmitters, hormones, light, electrical potential, extracellular matrix, neurotrophic factors, and cytokines, can produce diverse physiological effects by regulating the phosphorylation of specific phosphor-proteins in their target cells. These extracellular signals modify the activity of protein kinases and/or phosphatases either directly (e.g. receptors with kinase activity) or via cascades of enzymatic reactions (e.g. receptor → G protein → enzyme ~ second messenger ~ protein kinase).
2.3. Kinases involved in α-synuclein phosphorylation
α-Syn phosphorylation can be induced by several kinases. Serine129 of α-Syn can be phosphorylated by G protein-coupled receptor kinases (GRK1, GRK2, GRK5, and GRK6) [61–63], casein kinases 1 and 2 (CK1 and CK2) [26, 64–69], and the polo-like kinases (PLKs) . Current studies have shown that, GRKs may also phosphorylate non-receptor substrates, comprising the four members of the Syn family (α-,β-,γ-Syn, and synoretin) in addition to phosphorylating agonist-occupied G protein-coupled receptors (GPCRs) . Overexpression of GRK2 or GRK5 in COS-1 cells, showed that these kinases phosphorylate α-Syn at serine129 . Endogenous GRK-induced phosphorylation of α-Syn at serine129 was demonstrated
The other group of kinases that phosphorylates α-Syn at serine129 is CK1 and CK2. This has been demonstrated in the yeast model , in mammalian cells [26, 68] and in rat primary cortical neurons . It has been suggested that phosphorylation of serine129 in α-Syn by CK2 may promote
2.4. Phosphorylation at serine129 modulates α-synuclein protein-protein interaction
The C-terminal domain of α-synuclein (residues 96–140) is an acidic tail of 43AA residues, containing 10 Glu and 5 Asp residues. C-terminal truncations of α-Syn induce aggregation, suggesting that C-terminal modifications might be involved in the pathology of α-Syn . An interaction between the C-terminal domain and the NAC region of α-Syn is postulated to be responsible for the inhibition of α-Syn aggregation. Moreover, there are several studies on the interaction of α-Syn C-terminal tail with different proteins [86–91]. McFarland et al.  were the pioneers to address this using targeted functional proteomics . The authors showed that the non-phosphorylated α-Syn peptide primarily interacts with proteins related to the mitochondrial electron transport chain (ETC) (complex I, III, and IV proteins of the ETC) . It was hypothesized that changes in α-Syn phosphorylation could represent a response to biochemical events associated with PD pathogenesis. Among these, mitochondrial complex I dysfunction, oxidative stress, and proteasome dysfunction are processes that are known to be involved in synucleinopathies [93, 94]. The low levels of pSyn under physiological conditions as well as the absence of other phosphorylated residues such as pY39, pS87 and pY125 [26, 49, 50] suggest a faster degradation of this form under normal conditions. In fact, the phosphorylation status of α-Syn was recently correlated with clearance mechanisms [95, 96]. Another group Chau et al.  too reported that α-Syn phosphorylation at serine129 is toxic to DA cells and both the levels of serine129 phosphorylated protein as well as its toxicity are increased with proteosomal inhibition, emphasizing the interdependence of these pathways in PD pathogenesis.
However, the pSyn has a greater affinity for certain cytoskeletal and presynaptic proteins associated with synaptic transmission and vesicle trafficking . Yin et al.  showed that α-Syn interacts with the switch region of Rab8a, a small guanine nucleotide-binding protein, in a serine129 phosphorylation-dependent manner; thus implicating its role in coordinating vesicle trafficking. Hara et al.  reported that serine129 phosphorylation of membrane-associated α-Syn modulates dopamine transporter function in a G protein-coupled receptor kinase-dependent manner. These observations suggest that pSyn could serve as a molecular switch to control α-Syn interaction with different protein partners and therefore may modulate the function of DA neurons. However, further investigations are required to assess the impact and the physiological consequences of serine129 phosphorylation on α-Syn interaction with other proteins, such as SNARE proteins [35, 100], cytoskeletal proteins (i.e. tubulin) [55, 101] and other amyloidogenic proteins (i.e. tau) [19, 102]. Jensen et al.  have hypothesized that an interaction between α-Syn and tau could link synaptic vesicles with microtubules. Tau has been shown to co-localize and interact directly with the Src PTK family member, Fyn . It is hypothesized that tau could bring Src PTK family members such as Fyn into closer proximity to α-Syn, thereby enhancing the activity of these kinases for α-Syn. Samuel et al.  showed that the membrane binding of α-Syn monomers was differentially affected by phosphorylation depending on the PD-linked mutation. WT α-Syn binding to presynaptic membranes was not affected by phosphorylation, while A30P α-Syn binding was greatly increased and A53T α-Syn was marginally lower, implicating the distal effects of the carboxyl terminal on amino-terminal membrane binding. The un-phosphorylated form of serine129 associates mainly with mitochondrial electron transport proteins, while the phosphorylated form associates with cytoskeletal, vesicular trafficking proteins and enzymes involved in protein serine phosphorylation . Further work by Sugeno et al.  using α-Syn-over expressing cells exposed to a low dose of rotenone as an environmental toxin, showed that phosphorylation of α-Syn at serine129 promoted intracellular aggregate-formation and induced ER stress that was followed by mitochondrial damage and apoptosis.
Phosphorylation also seems to play an important role in the regulation of α-Syn axonal transport as the serine129D mutation significantly decreases its rate of transport in neurons, probably due to the modulation of α-Syn interaction with motor and/or accessory proteins involved in this process . Moreover, the interplay between the different phosphorylated residues could increase the diversity in the possible protein interactors. Several differences were observed in the set of proteins that were found to interact with serine129 and Y125-phosphorylated forms of α-Syn . S129 and Y125 residues both residing in the C-terminal region of α-Syn have been implicated in the majority of α-Syn interactions with proteins [103, 108, 109], reinforcing the significance of phosphorylation in these residues in modulating the biological role of α-Syn. All these findings together suggest that phosphorylation of α-Syn at serine129 has a widespread effect on protein-protein interaction of α-Syn.
Phosphorylation also seems to alter the subcellular localization of α-Syn. pSyn was found to be preferentially localized in the nuclei of DA neurons in rat and mouse models of synucleinopathy [67, 100]. In studies using PD rat models, the phospho-resistant S129A was found to be localized in the nucleus at higher levels than the S129D form, and was found to correlate with enhanced toxicity [110, 111]. Our group too demonstrated the nuclear localization of pSyn in SH-SY5Y cells under 6-hydroxydopamine toxicity . Gonçalves and Outeiro  showed that S129 phosphorylation modulates the shuttling of α-Syn between nucleus and cytoplasm in human neuroglioma cells, using photo-activatable green fluorescent protein as a reporter. Moreover, the study showed that co-expression of α-Syn with different kinases altered the translocation dynamics of the protein. While G protein-coupled receptor kinase 5 (GRK5) promotes the nuclear localization of α-Syn, PLK2 and three modulate the shuttling of the protein between the nucleus and cytoplasm . This difference reflects different α-Syn phosphorylation patterns in serine129 and/or other residues. Although the function of α-Syn in the nucleus is still unclear, it appears to be related to pathological insults. In particular, nuclear localization of α-Syn increases under oxidative stress conditions [112, 114, 115]. Nuclear α-Syn interacts with histones, inhibits acetylation, and promotes neurotoxicity [116, 117]. Furthermore, α-Syn may act as a transcriptional regulator, binding promoters such as PGC1-α, a master regulator of mitochondrial gene expression . The significance of pSyn in regulating nuclear proteins still needs to be unraveled.
2.5. Oxidative stress and α-Syn phosphorylation
Oxidative stress can increase α-Syn phosphorylation . Perfeito et al.  showed through an
2.6. α-Syn phosphorylation at serine129 and cellular events
The role of α-Syn phosphorylation in the cellular pathogenesis of PD remains debated [92, 110, 111, 121, 122]. This apparent controversy is due to the fact that phosphomimics (S129D/E) do not reproduce the exact properties of the endogenous authentically phosphorylated α-Syn [122–124]. The expression of a variant showing prevention of phosphorylation by site-directed mutagenesis of serine129 to alanine (S129A) caused an increase in α-Syn inclusions and toxicity  On the other hand, several investigators have reported that the expression of S129A mutant protein led to fewer inclusions [66, 94, 110]. It has also been reported that the expression of phosphorylation mimicking serine129 to the aspartate (S129D) variant does not show DA deficits [92, 110, 111, 121, 123]. Hence, several groups have sought to address the issue by overexpressing α-Syn and using siRNA for its natural kinases [99, 118, 124]. As discussed in the earlier section, among the kinases primarily responsible for the α-Syn phosphorylation at serine129 are CKs, GRKs, LRRK2, and PLKs. The modulation of phosphorylation of α-Syn has also been reported by targeting the kinases in A53T mutant α-Syn expressing cells [99, 118, 124–126]. siRNA studies targeting kinases such as PLK, GRK2, and CK2 have been used to study the effect of phosphorylated α-synuclein on WT and A53T mutant α-synuclein expressing cells [99, 118, 124, 125, 127]. These studies have shown the effect of α-Syn phosphorylation with respect to ROS generation, mitochondrial alterations, proteasomal changes, and dopamine transport. The work of Perfeito et al.  suggest that stimuli that promote ROS formation and mitochondrial alterations highly correlate with mutant α-Syn phosphorylation at serine129, which may precede cell degeneration in PD. Similarly, we have shown in our recent work that at sub-lethal 6-hydroxydopamine concentrations, the decrease in resting vesicles (VMAT2) and vesicular dopamine release are not attributable to apoptotic cell death and occur concomitantly with the phosphorylation of α-Syn .
2.7. α-Syn phosphorylation at serine129 during PD pathogenesis: an early or late event?
The evidence of pSyn accumulation in the brain has been collected largely from post mortem analysis and it fails to answer if this accumulation occurs during the early or late stages of synucleinopathies. In a recent work, Walker et al.  investigated how pSyn levels and solubility change in cingulate and temporal cortex of DLB patients, at different stages of the disease. The authors reported a progressive accumulation of pSyn-immunoreactive species in diseased brains compared to healthy controls, as well as a positive correlation between pSyn levels and the severity of disease symptoms. A similar study using brain samples from PD patients also reported a drastic accumulation of pSyn-positive inclusions in different brain regions at the late stages of the disease . Together, these results suggest that the occurrence of pSyn is linked to the severity of disease progression.
In our recent work, we demonstrated using biophysical and biochemical analysis in an
2.8. pSyn in human fluids and PNS of synucleinopathies
Several studies in the field of PD and diagnosis of Parkinsonism are based on the fundamental molecular events associated with or without LBs. Total α-Syn quantification in the CSF of PD, DLB, and MSA patients in comparison to healthy controls has been proposed as a biomarker for α-Syn-related disorders [129–131]. However, an ideal biomarker for a particular disease must be easy to detect, and also reflect disease onset and progression with associated primary changes. A longitudinal study conducted by Foulds et al.  in the blood plasma of patients suffering from PD showed that total α-Syn in blood plasma of PD patients remained similar to that in normal individuals, but the level of α-Syn phosphorylated at serine129 was significantly higher in PD patients. Statistical analysis confirmed the usefulness of plasma levels of pSyn in discriminating patients with PD from healthy controls. In addition, pSyn inclusions were also detected in the PNS which might also serve as a useful diagnostic test for PD and related synucleinopathies. Work from two independent groups on skin biopsies showed that the majority of PD patients had accumulation of pSyn in small and large nerve fibers, while no signal was detected in healthy controls and in MSA or essential tremor control subjects [133, 134]. This cutaneous pathology was correlated with the progression of disease symptoms suggesting the use of this peripheral marker as a biomarker for the disease . Presence of pSyn immunoreactivity was detected in gastric, duodenal and colonic biopsies [136, 137]. Hilton et al.  further reports that this accumulation of pSyn in the bowels of patients is detected in the pre-clinical phase of PD. Taken together, these reports suggest that accumulation of pSyn might provide a more reliable biomarker to detect PD at early stages and further discriminate between synucleinopathies, compared to total α-Syn.
In comparison to the relatively small number of genes, the large diversity of the proteome is achieved mainly by post-translational protein modifications, phosphorylation being the most widespread. Since the C-terminal region of α-Syn is involved in interaction with proteins [103, 104, 109] and metal ions [138–140], any phosphorylation in this site can alter its interaction capability . The significance of α-Syn phosphorylation at serine129 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 and related disorders. Since some
De Lau LM, Breteler MM. Epidemiology of Parkinson's disease. The Lancet Neurology. 2006;5(6):525-535
Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, et al. Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000;25:239-252
Alexander GE. Biology of PD: Pathogenesis & pathophysiology of a multisystem neurodegenerative disorder. Dialogues in Clinical Neuroscience. 2004;6(3):259-280
Gesi M, Soldani P, Giorgi FS, Santinami A, Bonaccorsi I, Fornai F. The role of the locus coeruleus in the development of PD. Neuroscience & Biobehavioral Reviews. 2000;24(6):655-668
Hornykiewicz O. Parkinson's disease and the adaptive capacity of the nigrostriatal dopamine system: Possible neurochemical mechanisms. Advances in Neurology1993;60:140-147
Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias R, et al. Initial clinical manifestations of PD: Features and pathophysiological mechanisms. The Lancet Neurology. 2009;8(12):1128-1139
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, et al. Mutation in the α-synclein gene identified in families with PD. Science. 1997;276:2045-2047
Kruger R, Kuhn W, Mller T, Woitalla D, Graeber M, Kösel S, et al. Ala53Pro mutation in the gene encoding α-synuclein in PD. Nature Genetics. 1998;18:106-108
Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, et al. The mutation, E46K of α-synuclein causes Parkinson and Lewy body dementia. Annals of Neurology. 2004;55:164-173
Singleton AB, Farrer M, Johnson J, Singleton A, Haugue S, et al. α-Synuclein locus triplication causes PD. Science. 2003;302:841
Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, et al. Dopaminergic loss and inclusion body formation in α-synuclein mice. Implications for neurodegenerative disorders. Science. 2000;287:1265-1269
Scherzer CR, Grass JA, Liao Z, Pepivani I, Zheng B, et al. GATA transcription factors directly regulate the PD-linked gene α-synuclein. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:10907-10912
Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, et al. Dopamine-modified α-synuclein blocks chaperone-mediated autophagy. The Journal of Clinical Investigation. 2008;118(2):777-788
El-Agnaf OMA, Salem SA, Paleologou KE, Curran MD, Gibson MJ, et al. Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for PD. The FASEB Journal. 2006;20:419-425
Beyer K. α-Synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Actaneuropathologica. 2006;112(3):237-251
Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T. The precursor protein of non-A component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron. 1995;14:467-475
Waxman EA, Giasson BI. Molecular mechanisms of α-synuclein neurodegeneration. Biochimicaet Biophysica Acta (BBA) – Molecular Basis of Disease. 2009;1792(7):616-624
Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America. 1993;90:11282-11286
Jakes R, Spillantini MG, Goedert MI. Identification of two distinct synucleins from human brain. FEBS Letters. 1994;345:27-32
George JM. The synucleins. Genome Biology. 2002;3:3002-3006
Chandra S, Chen X, Rizo J, Jahn R, Südho TC. A broken-helix in folded α-synuclein. Journal of Biological Chemistry. 2003;278:15313-15318
Davidson WS, Jonas A, Clayton DF, George JM. Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. Journal of Biological Chemistry. 1998;273:9443-9449
Eliezer D, Kutluay E, Bussell R, Jr, Browne G. Conformational properties of α-synuclein in its free and lipid-associated states. Journal of Molecular Biology. 2001;307:1061-1073
Giasson BI, Murray IVJ, Trojanowski JQ, Lee VM. A hydrophobic stretch of 12 amino acid residues in the middle of synuclein is essential for filament assembly. Journal of Biological Chemistry. 2001;276:2380-2386
El-Agnaf OMA, Irvine GB. Aggregation and neurotoxicity of α-synuclein and related peptides. Biochemical Society Transactions.2002;30:559-565
Okochi M, Walter J, Koyama A, Nakajo S, Baba M, et al. Constitutive phosphorylation of the PD associated α-synuclein. Journal of Biological Chemistry. 2000;275:390-397
Souza JM, Giasson BI, Lee VM, Ischiropoulos H. Chaperone-like activity of synucleins. FEBS Letters. 2000;474:116-119
Kim TD, Paik SR, Yang CH. Structural and functional implications of C-terminal regions of α-synuclein. Biochemistry. 2002;41:13782-13790
Park SM, Jung HY, Kim TD, Park JH, Yang CH, Kim, J. Distinct roles of the N-terminal-binding domain and the C-terminal-solubilizing domain of α-synuclein, a molecular chaperone. Journal of Biological Chemistry. 2002;277:28512-28520
Uversky VN. Neuropathology, biochemistry, and biophysics of synuclein aggregation. Journal of Neurochemistry. 2007;103:17-37
Lavedan C. The synuclein family. Genome Research. 1998;8:871-880
Cavallarin N, Vicario M, Negro A. The role of phosphorylation in synucleinopathies: Focus on PD. CNS & Neurological Disorders-Drug Targets. 2010;9(4):471-481.
Auluck PK, Caraveo G, Lindquist S. α-Synuclein: Membrane interactions and toxicity in PD. Annual Review of Cell and Developmental Biology. 2010;26:211-233
Greten-Harrison B, Polydoro M, Morimoto-Tomita M, Diao L, Williams AM, et al. αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proceedings of the National Academy of Sciences. 2010;107(45):19573-19578
Drolet RE, Behrouz B, Lookingland KJ, Goudreau JL. Mice lacking α-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology. 2004;25(5):761-769
Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, et al. Increased expression of α-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010;65(1):66-79
Xu J, Kao S-Y, Lee FJ, Song W, Jin L-W, Yankner BA. Dopamine-dependent neurotoxicity of α-synuclein: A mechanism for selective neurodegeneration in PD. Nature Medicine. 2002;8:600-606
Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ. A role for α-synuclein in the regulation of dopamine biosynthesis. Journal of Neuroscience. 2002;22:3090-3099
Mazzulli JR, Zunke F, Tsunemi T, Toker NJ, Jeon S, et al. Activation of β-glucocerebrosidase reduces pathological α-synuclein and restores lysosomal function in Parkinson's patient midbrain neurons. Journal of Neuroscience.2016;36(29):7693-7706
Janda E, Isidoro C, Carresi C, Mollace V. Defective autophagy in PD: Role of oxidative stress. Molecular Neurobiology. 2012;46(3):639-661
McCormack A, Chegeni N, Chegini F, Colella A, Power J, Keating D, Chataway T. Purification of α-synuclein containing inclusions from human post mortem brain tissue. Journal of Neuroscience Methods. 2016;266:141-150
Manning G, Plowman GD, Hunter T, Sudarsanam S. Evolution of protein kinase signaling from yeast to man. Trends in Biochemical Sciences. 2002;27:514-520
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912-1934
Navarro J, del Moral R, Marijuán PC. Charting the Signaling Pathways of the Neuron. The Wiley Handbook of Evolutionary Neuroscience; first edition, John wiley &sons Ltd. 2016 Dec 12:49.
Cieśla J, Frączyk T, Rode W. Phosphorylation of basic amino acid residues in proteins: Important but easily missed. Acta Biochimica Polonica. 2011;58(2):137-148
Deutscher J, Saier Jr MH. Ser/Thr/Tyr protein phosphorylation in bacteria–for long time neglected, now well established. Journal of Molecular Microbiology and Biotechnology. 2006;9(3-4):125-131
Fuhrmann J, Subramanian V, Kojetin DJ, Thompson PR. Activity-based profiling reveals a regulatory link between oxidative stress and protein arginine phosphorylation. Cell Chemical Biology. 2016;23(8):967-977
Matthews HR. Protein kinases and phosphatases that act on histidine, lysine, or arginine residues in eukaryotic proteins: A possible regulator of the mitogen-activated protein kinase cascade. Pharmacology & Therapeutics. 1995;67(3):323-350
Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, et al. Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease. Journal of Biological Chemistry. 2006;281:29739-29752
Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, et al. α-Synuclein is phosphorylated in synucleinopathy lesions.Nature Cell Biology. 2002;4:160-164
Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, et al. Subcellular localization of wild-type and Parkinson's disease-associated mutant α-synuclein in human and transgenic mouse brain. Journal of Neuroscience. 2000;20:6365-6373
Chen L, Feany MB. α-Synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of PD. Nature Neuroscience. 2005;8:657-663
Takahashi M, Kanuka H, Fujiwara H, Koyama A, Hasegawa M, et al. Phosphorylation of α-synuclein characteristic of synucleinopathy lesions is recapitulated in α-synuclein transgenic Drosophila. Neuroscience Letters. 2003;336:155-158
Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H. Overexpression of α-synuclein in rat SNpc results in loss of dopaminergic neurons, phosphorylation of α-synuclein and activation of caspase-9: Resemblance to pathogenetic changes in PD. Journal of Neurochemistry. 2004;91:451-461
Hasegawa M, Fujiwara H, Nonaka T, Wakabasyashi KK, Takahashi H, et al. Phosphorylated α-synuclein is ubiquitinated in synucleopathy lesions. Journal of Biological Chemistry. 2002;277:49071-49076
Arima K, Hirai S, Sunohara N, Aoto K, Izumiyama Y, et al. Cellular co-localization of phosphorylated tau- & NACP/-synuclein-epitopes in Lewy bodies in sporadic PD and in dementia with Lewy bodies. Brain Research. 1999;843:153-161
Hirai Y, Fujita SC, Iwatsubo T, Hasegawa M. Phosphorylated α-Syn in normal mouse brain. FEBS Letters. 2004;572:227-232
Sherwood L. Human Physiology: From Cells to Systems. Cengage learning Brooks/Cole; 2015. ISBN-13: 978-0-495-39184-5
Dobson KL, Bellamy TC. Glial Cells. In Essentials of Cerebellum and Cerebellar Disorder. Springer International Publishing. 2016;219-223.
Peters DG, Connor JR. Introduction to cells comprising the nervous system In: Glycobiology of the Nervous System. New York: Springer. 2014. pp. 33-45
Arawaka S, Wada M, Goto S, Karube H, Sakamoto M, Ren CH, et al. The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic PD. Journal of Neuroscience. 2006;26:9227-9238
Pronin AN, Morris AJ, Surguchov A, Benovic JL. Synucleins are a novel class of substrates for G proteincoupled receptor kinases. Journal of Biological Chemistry. 2000;275:26515-26522
Sakamoto M, Arawaka S, Hara S, Sato H, Cui C, Machiya Y, et al. Contribution of endogenous G-protein-coupled receptor kinases to Ser129 phosphorylation of α-synuclein in HEK293 cells. Biochemical and Biophysical Research Communications. 2009;384:378-382
Ishii A, Nonaka T, Taniguchi S, Saito T, Arai T, Mann D, et al. Casein kinase 2 is the major enzyme in brain that phosphorylates Ser129 of human α-synuclein: Implication for α-synucleinopathies. FEBS Letters. 2007;581:4711-4717
Takahashi M, Ko LW, Kulathingal J, Jiang P, Sevlever D, Yen SH. Oxidative stress-induced phosphorylation, degradation and aggregation of α-synuclein are linked to upregulated CK2 & cathepsin D. European Journal of Neuroscience. 2007;26:863-874
Smith WW, Margolis RL, Li X, Troncoso JC, Lee MK, Dawson VL, et al. α-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. Journal of Neuroscience. 2005;25:5544-5555
Wakamatsu M, Ishii A, Ukai Y, Sakagami J, Iwata S, Ono M, et al. Accumulation of phosphorylated α-synuclein in dopaminergic neurons of transgenic mice that express human α-synuclein. Journal of Neuroscience Research. 2007;85:1819-1825
Waxman EA, Giasson BI. Specificity and regulation of casein kinase-mediated phosphorylation of α-synuclein. Journal of Neuropathology & Experimental Neurology. 2008;67:402-416
Zabrocki P, Bastiaens I, Delay C, Bammens T, Ghillebert R, Pellens K, et al. Phosphorylation, lipid raft interaction and traffic of α-synuclein in a yeast model for Parkinson. Biochimica et Biophysica Acta. 2008;1783:1767-1780
Inglis KJ, Chereau D, Brigham EF, Chiou SS, Schobel S, Frigon NL, et al. Polo-like kinase 2 (PLK2) phosphorylates α-synuclein at serine 129 in central nervous system. Journal of Biological Chemistry. 2009;284:2598-2602
Liu P, Wang X, Gao N, Zhu H, Dai X, Xu Y, et al. G protein-coupled receptor kinase 5, overexpressed in the α-synuclein up-regulation model of PD, regulates bcl-2 expression. Brain Research. 2010;1307:134-141
Tarantino P, De Marco EV, Annesi G, Rocca FE, Annesi F, Civitelli D, et al. Lack of association between G-protein coupled receptor kinase5 gene & PD. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2011; 156B:104-107
Nishie M, Mori F, Fujiwara H, Hasegawa M, Yoshimoto M, Iwatsubo T, et al. Accumulation of phosphorylated α-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy. Acta Neuropathologica. 2004;107:292-298
Waxman EA, Giasson BI. Characterization of kinases involved in the phosphorylation of aggregated α-synuclein. Journal of Neuroscience Research. 2011;89:231-247
Ryu, MY, Kim DW, Arima K, Mouradian MM, Kim SU, and Lee G. Localization of CKII beta subunits in Lewy bodies of PD. Journal of the Neurological Sciences. 2008;266:9-12
Paleologou KE, Oueslati A, Shakked G, Rospigliosi CC, Kim HY, Lamberto GR, et al. Phosphorylation at S87 is enhanced in synucleinopathies, inhibits α-synuclein oligomerization, and influences synuclein-membrane interactions. Journal of Neuroscience. 2010;30:3184-3198
Mbefo MK, Paleologou KE, Boucharaba A, Oueslati A, Schell H, Fournier M, et al. Phosphorylation of synucleins by members of the polo-like kinase family. Journal of Biological Chemistry. 2010;285:2807-2822
Ng SS, Papadopoulou K, McInerny CJ. Regulation of gene expression and cell division by Polo-like kinases. Current Genetics. 2006;50:73-80
Buck K, Landeck N, Ulusoy A, Majbour NK, El-Agnaf OM, Kirik D. Ser129 phosphorylation of endogenous α-synuclein induced by overexpression of polo-like kinases 2 and 3 in nigral dopamine neurons is not detrimental to their survival and function. Neurobiology of Disease. 2015;30(78):100-114
Aubele DL, Hom RK, Adler M, Galemmo RA, Bowers S, et al. Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce α-synuclein phosphorylation in rat brain. ChemMedChem. 2013;8(8):1295-1313
Kauselmann G, Weiler M, Wulff P, Jessberger S, Konietzko U, et al. The polo-like protein kinases Fnk & Snk associate with a Ca2+ and integrin-binding protein and are regulated dynamically with synaptic plasticity. EMBO Journal. 1999;18:5528-5539
Seeburg DP, Pak D, Sheng M. Polo-like kinases in the nervous system. Oncogene. 2005;24:292-298
Qing H, Wong W, McGeer EG, McGeer PL. Lrrk2 phosphorylates α-synuclein at serine 129: PD implications. Biochemical and Biophysical Research Communications. 2009;387:149-152
Guerreiro PS, Huang Y, Gysbers A, Cheng D, Gai WP, Outeiro TF, et al. LRRK2 interactions with α-synuclein in PD brain and in cell models. Journal of Molecular Medicine (Berlin). 2013;91:513-522
Venda LL, Cragg SJ, Buchman VL, Wade-Martins R. α-Synuclein and dopamine at the crossroads of PD. Trends in Neurosciences. 2010;33(12):559-568
Duda JE, Giasson BI, Mabon ME, Miller DC, Golbe LI, Lee VM, Trojanowski JQ. Concurrence of α-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathologica. 2002;104(1):7-11
Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron. 2002;34(4):521-533
Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, et al. Biochemical & pathological characterization of Lrrk2. Annals of Neurology. 2006;59(2):315-322
Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, et al. The E46K mutation in α-synuclein increases amyloid fibril formation. Journal of Biological Chemistry. 2005;280(9):7800-7807
Kosik KS, Orecchio LD, Binder L, Trojanowski JQ, Lee VY, Lee G. Epitopes that span the tau molecule are shared with paired helical filaments. Neuron.1988;1(9):817-825
Otvos L, Feiner L, Lang E, Szendrei GI, Goedert M, Lee VM. Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404. Journal of Neuroscience Research. 1994;39(6):669-673
McFarland NR, Fan Z, Xu K, Schwarzschild MA, Feany MB, Hyman BT, McLean PJ. α-synuclein S129 phosphorylation mutants do not alter nigrostriatal toxicity in a rat model of PD. Journal of Neuropathology and Experimental Neurology.2009;68:515-524
Lashuel HA, Overk CR, Oueslati A, Masliah E. The many faces of α-synuclein: From structure and toxicity to therapeutic target. Nature Reviews Neuroscience. 2013;14:38-48
Lee VM, Trojanowski JQ. Mechanisms of PD linked to pathological α-synuclein: New targets for drug discovery. Neuron. 2006;52:33-38
Mahul-Mellie AL, Fauvet B, Gysbers A, Dikiy I, Oueslati A, Georgeon S, et al. c-Abl phosphorylates α-synuclein & regulates its degradation, implication for α-synuclein clearance & contribution to the pathogenesis of PD. Human Molecular Genetics. 2014;23(11):2858-2879
Oueslati A, Schneider BL, Aebischer P, Lashuel HA. Polo-like kinase 2 regulates selective autophagic α-synuclein clearance & suppresses its toxicity in vivo. Proceedings of the National academy of Sciences of the United States of America. 2013;110:E3945-E3954
Chau KY, Ching HL, Schapira AH, and Cooper JM. Relationship between α-synuclein phosphorylation, proteasomal inhibition & cell death: Relevance to PD pathogenesis. Journal of Neurochemistry. 2009;110:1005-1013
Yin G, Lopes da Fonseca T, Eisbach SE, Anduaga AM, Breda C, et al. α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. Neurobiology of Disease. 2014;70:149-161
Hara S, Arawaka S, Sato H, Machiya Y, Cui C, Sasaki A, Koyama S, Kato T. Serine 129 phosphorylation of membrane-associated α-synuclein modulates dopamine transporter function in a G protein-coupled receptor kinase-dependent manner. Molecular Biology of the Cell. 2013;24:1649-1660, S1641-S1643.
Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H. Overexpression of α-synuclein in rat SNpc results in loss of dopaminergic neurons, phosphorylation of α-synuclein & activation of caspase-9: Resemblance to pathogenetic changes in PD. Journal of Neurochemistry. 2004;91:451-461
Sampathu DM, Giasson BI, Pawlyk AC, Trojanowski JQ, Lee VM. Ubiquitination of α-synuclein is not required for formation of pathological inclusions in α-synucleinopathies. The American Journal of Pathology. 2003;163(1):91-100
Buchman VL, Hunter HJ, Pinõn LG, Thompson J, Privalova EM, Ninkina NN, Davies AM. Persyn, a member of the synuclein family, has a distinct pattern of expression in the developing nervous system. Journal of Neuroscience. 1998;18(22):9335-9341
Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, & Jakes R. α-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. Journal of Biological Chemistry. 1999;274:25481-25489
Bhaskar K, Yen SH, Lee G. Disease-related modifications in tau affect the interaction between Fyn & tau. Journal of Biological Chemistry. 2005;280:35119-35125
Samuel F, Flavin WP, Iqbal S, Pacelli C, Renganathan SD, Trudeau LE, Campbell EM, Fraser PE, Tandon A. Effects of Serine 129 phosphorylation on α-synuclein aggregation, membrane association, and internalization. Journal of Biological Chemistry. 2016;291(9):4374-4385
Sugeno N, Takeda A, Hasegawa T, Kobayashi M, Kikuchi A, Mori F, Wakabayashi K, Itoyama Y. Serine 129 phosphorylation of α-synuclein induces unfolded protein response mediated cell death. Journal of Biological Chemistry. 2008;283:23179-23188
Saha AR, Hill J, Utton MA, Asuni AA, Ackerley S, Grierson AJ., et al. Parkinson’s disease α-synuclein mutations exhibit defective axonal transport in cultured neurons. Journal of Cell Science. 2004;117:1017-1024
Fernandez CO, Hoyer W, Zweckstetter M, Jares-Erijman EA, Subramaniam V, Griesinger C, et al. NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation. EMBO Journal. 2004;23:2039-2046
Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, et al. Initiation and synergistic fibrillization of tau & α-synuclein. Science. 2003;300:636-640
da Azeredo SS, Schneider BL, Cifuentes-Diaz C, et al. Phosphorylation does not prompt, nor prevent, the formation of α-synuclein toxic species in a rat model of PD. Human Molecular Genetics. 2009;18:872-887
Gorbatyuk OS, Li S, Sullivan LF, Chen W, Kondrikova G, Manfredsson FP, Mandel RJ, Muzyczka N. The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of PD. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:763-768
Ganapathy K, Datta I, Sowmithra S, Joshi P, and Bhonde R. Influence of 6-hydroxydopamine toxicity on α-Synuclein phosphorylation, resting vesicle expression, and vesicular dopamine release. Journal of Cellular Biochemistry. 2016;9999:1-18
Gonçalves S, Outeiro TF. Assessing the subcellular dynamics of α-synuclein using photoactivation microscopy. Molecular Neurobiology. 2013;47:1081-1092
Monti B, Gatta V, Piretti F, Raffaelli SS, Virgili M, Contestabile A. Valproic acid is neuroprotective in the rotenone rat model of PD: Involvement of α-synuclein. Neurotoxicity Research. 2010;17(2):130-141
Siddiqui A, Chinta SJ, Mallajosyula JK, Rajagopolan S, Hanson I, et al. Selective binding of nuclear α-synuclein to the PGC1 α promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: Implications for PD. Free Radical Biology and Medicine. 2012;53:993-1003
Goers J, Manning-Bog AB, McCormack AL, Millett IS, Doniach S, Di Monte, DA, et al. Nuclear localization of α-synuclein and its interaction with histones. Biochemistry. 2003;42:8465-8471
Kontopoulos E, Parvin JD, Feany MB. α-Synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Human Molecular Genetics. 2006;15:3012-3023
Perfeito R, Lázaro DF, Outeiro TF, Rego AC. Linking α-synuclein phosphorylation to reactive oxygen species formation and mitochondrial dysfunction in SH-SY5Y cells. Molecular and Cellular Neuroscience. 2014;62:51-59
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science. 2004;305(5688):1292-5
Schel H, Hasegawa T, Neumann M, Kahle PJ. (2009) Nuclear & neuritic distribution of serine-129 phosphorylated α-synuclein in transgenic mice. Neuroscience. 2009;160:796-804
Dyllick-Brenzinger M, D'Souza CA, Dahlmann B, Kloetzel PM, Tandon A. Reciprocal effects of α-synuclein overexpression and proteasome inhibition in neuronal cells and tissue. Neurotoxicity Research. 2010;17:215-227
Febbraro F, Sahin G, Farran A, Soares S, Jensen PH, Kirik D, Romero-Ramos M. Ser129D mutant α-synuclein induces earlier motor dysfunction while S129A results in distinctive pathology in a rat model of PD. Neurobiology of Disease. 2013;56:47-58
Oueslati A, Fournier M, Lashuel HA. Role of post-translational modifications in modulating the structure, function & toxicity of α-synuclein: Implications for PD pathogenesis & therapies. Progress in Brain Research. 2010;183:115-145
Paleologou KE, Schmid AW, Rospigliosi CC, Kim HY, Lamberto GR, et al. Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of α-synuclein. Journal of Biological Chemistry. 2008;283:16895-16905
Machiya Y, Hara S, Arawaka S, Fukushima S, Sato H, et al. Phosphorylated α-synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin-independent manner. Journal of Biological Chemistry. 2010;285:40732-40744
Gurevich EV, Tesmer JJG, Mushegian A, Gurevich VV. G-protein-coupled receptor kinases: More than just kinases and not only for GPCRs. Pharmacology & Therapeutics. 2012;133(1):40-69
Walker DG, Lue LF, Adler CH, Shill HA, Caviness JN, et al. Arizona Parkinson Disease C. Changes in properties of serine 129 phosphorylated α-synuclein with progression of Lewy-type histopathology in human brains. Experimental Neurology. 2013;240:190-204
Zhou J, Broe M, Huang Y, Anderson JP, Gai WP, et al. Changes in the solubility and phosphorylation of α-synuclein over the course of PD. Acta Neuropathologica. 2011;121:695-704
Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, et al. DJ-1 and α-synuclein in human cerebrospinal fluid as biomarkers of PD. Brain. 2010;133(3):713-726
Kang JH, Irwin DJ, Chen-Plotkin AS, Siderowf A, Caspell C, et al. Association of cerebrospinal fluid β-amyloid 1-42, T-tau, P-tau181, and α-synuclein levels with clinical features of drug-naive patients with early PD. JAMA Neurology. 2013;70(10):1277-1287
Mollenhauer B, Cullen V, Kahn I, Krastins B, Outeiro TF, et al. Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Experimental Neurology. 2008;213(2):315-325
Foulds PG, Diggle P, Mitchell JD, Parker A, Hasegawa M, et al. A longitudinal study on α-synuclein in blood plasma as a biomarker for PD. Scientific Reports. 2013;3:2540
Stewart T, Sossi V, Aasly JO, Wszolek ZK, Uitti RJ, et al. Phosphorylated α-synuclein in PD: Correlation depends on disease severity. Acta Neuropathologica Communications. 2015;3(1):7
Wang Y, Shi M, Chung KA, Zabetian CP, Leverenz JB, et al. Phosphorylated α-synuclein in PD. Science Translational Medicine. 2012;4(121):121
Doppler K, Ebert S, Uceyler N, Trenkwalder C, Ebentheuer J, et al. Cutaneous neuropathy in PD: A window into brain pathology. Acta Neuropathologica. 2014;128:99-109
Pouclet H, Lebouvier T, Coron E, Neunlist M, Derkinderen P. Lewy pathology in gastric and duodenal biopsies in PD. Movement Disorders. 2012;27:708
Hilton D, Stephens M, Kirk L, Edwards P, Potter R, et al. Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of PD. Acta Neuropathologica. 2014;127:235-241
Brown DR. Interactions between metals & α-synuclein function or artefact? FEBS Journal. 2007;274(15):3766-3774
Hyun-Ju SH, Ju-Hyun LE, Chang CS, Jongsun KI. Copper (II)-induced self-oligomerization of α-synuclein. Biochemical Journal. 1999;340(3):821-828
Paik SR, Shin HJ, Lee JH. Metal-catalyzed oxidation of α-synuclein in the presence of copper (II) & hydrogen peroxide. Archives of Biochemistry and Biophysics. 2000;378(2):269-277