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Fox Foundation for Parkinson\u2019s Disease Research","award":["19K07097"],"award-info":[{"award-number":["19K07097"]}]},{"name":"The Michael J. Fox Foundation for Parkinson\u2019s Disease Research","award":["22K06644"],"award-info":[{"award-number":["22K06644"]}]},{"name":"The Michael J. Fox Foundation for Parkinson\u2019s Disease Research","award":["JP21dm0107071"],"award-info":[{"award-number":["JP21dm0107071"]}]},{"name":"the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development, AMED","award":["19K07097"],"award-info":[{"award-number":["19K07097"]}]},{"name":"the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development, AMED","award":["22K06644"],"award-info":[{"award-number":["22K06644"]}]},{"name":"the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development, AMED","award":["JP21dm0107071"],"award-info":[{"award-number":["JP21dm0107071"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>\u03b1-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the SNCA gene. Missense mutations and gene duplications in the SNCA gene cause hereditary Parkinson\u2019s disease. Highly phosphorylated and abnormally aggregated \u03b1-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson\u2019s disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated \u03b1-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most \u03b1-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated \u03b1-synuclein in Lewy bodies of patients with Parkinson\u2019s disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in \u03b1-synucleinopathy. Consequently, this review focuses on the pathogenic impact of \u03b1-synuclein phosphorylation and its kinases during the neurodegeneration process in \u03b1-synucleinopathy.<\/jats:p>","DOI":"10.3390\/ijms23116216","type":"journal-article","created":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T12:48:31Z","timestamp":1654087711000},"page":"6216","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":106,"title":["Pathogenic Impact of \u03b1-Synuclein Phosphorylation and Its Kinases in \u03b1-Synucleinopathies"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5916-7847","authenticated-orcid":false,"given":"Ichiro","family":"Kawahata","sequence":"first","affiliation":[{"name":"Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David I.","family":"Finkelstein","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8526-2824","authenticated-orcid":false,"given":"Kohji","family":"Fukunaga","sequence":"additional","affiliation":[{"name":"Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"},{"name":"BRI Pharma Inc., Sendai 982-0804, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.1523\/JNEUROSCI.08-08-02804.1988","article-title":"Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal","volume":"8","author":"Maroteaux","year":"1988","journal-title":"J. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/35081564","article-title":"Alpha-synuclein and neurodegenerative diseases","volume":"2","author":"Goedert","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"30473","DOI":"10.1038\/srep30473","article-title":"A small-angle X-ray scattering study of alpha-synuclein from human red blood cells","volume":"6","author":"Araki","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.jmb.2008.03.017","article-title":"Characterization of conformational and dynamic properties of natively unfolded human and mouse alpha-synuclein ensembles by NMR: Implication for aggregation","volume":"378","author":"Wu","year":"2008","journal-title":"J. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1016\/j.bbamem.2015.06.021","article-title":"alpha-Synuclein interactions with phospholipid model membranes: Key roles for electrostatic interactions and lipid-bilayer structure","volume":"1848","author":"Pirc","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hasegawa, T., Konno, M., Baba, T., Sugeno, N., Kikuchi, A., Kobayashi, M., Miura, E., Tanaka, N., Tamai, K., and Furukawa, K. (2011). The AAA-ATPase VPS4 regulates extracellular secretion and lysosomal targeting of alpha-synuclein. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0029460"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.bbrc.2006.08.024","article-title":"Decreased alpha-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson\u2019s disease","volume":"349","author":"Tokuda","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1096\/fj.03-1449com","article-title":"Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson\u2019s disease","volume":"20","author":"Salem","year":"2006","journal-title":"FASEB J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/nrneurol.2009.135","article-title":"Biological fluid biomarkers in neurodegenerative parkinsonism","volume":"5","author":"Eller","year":"2009","journal-title":"Nat. Rev. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"25481","DOI":"10.1074\/jbc.274.36.25481","article-title":"alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356","volume":"274","author":"Jensen","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1126\/science.1082324","article-title":"Initiation and synergistic fibrillization of tau and alpha-synuclein","volume":"300","author":"Giasson","year":"2003","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7281","DOI":"10.1523\/JNEUROSCI.0490-10.2010","article-title":"Synergistic Interactions between Abeta, tau, and alpha-synuclein: Acceleration of neuropathology and cognitive decline","volume":"30","author":"Clinton","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.15252\/embj.201591397","article-title":"alpha-synuclein assemblies sequester neuronal alpha3-Na+\/K+-ATPase and impair Na+ gradient","volume":"34","author":"Shrivastava","year":"2015","journal-title":"EMBO J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"344","DOI":"10.3389\/fnins.2018.00344","article-title":"Import and Export of Misfolded alpha-Synuclein","volume":"12","author":"Rodriguez","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"aah3374","DOI":"10.1126\/science.aah3374","article-title":"Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3","volume":"353","author":"Mao","year":"2016","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10240","DOI":"10.1096\/fj.201802051R","article-title":"Extracellular alpha-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis","volume":"33","author":"Kobayashi","year":"2019","journal-title":"FASEB J."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kawahata, I., Bousset, L., Melki, R., and Fukunaga, K. (2019). Fatty Acid-Binding Protein 3 is Critical for alpha-Synuclein Uptake and MPP(+)-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215358"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100663","DOI":"10.1016\/j.jbc.2021.100663","article-title":"An alpha-synuclein decoy peptide prevents cytotoxic alpha-synuclein aggregation caused by fatty acid binding protein 3","volume":"296","author":"Fukui","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kawahata, I., Sekimori, T., Wang, H., Wang, Y., Sasaoka, T., Bousset, L., Melki, R., Mizobata, T., Kawata, Y., and Fukunaga, K. (2021). Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated alpha-Synuclein Uptake in Cultured Dopaminergic Neurons. Biomedicines, 9.","DOI":"10.3390\/biomedicines9010049"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.jphs.2021.12.003","article-title":"Impact of fatty acid-binding proteins and dopamine receptors on alpha-synucleinopathy","volume":"148","author":"Kawahata","year":"2022","journal-title":"J. Pharmacol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1042\/bj3400821","article-title":"Copper(II)-induced self-oligomerization of alpha-synuclein","volume":"340","author":"Paik","year":"1999","journal-title":"Biochem. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3766","DOI":"10.1111\/j.1742-4658.2007.05917.x","article-title":"Interactions between metals and alpha-synuclein\u2014Function or artefact?","volume":"274","author":"Brown","year":"2007","journal-title":"FEBS J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"36328","DOI":"10.1038\/srep36328","article-title":"\u03b1-Synuclein enhances histone H3 lysine-9 dimethylation and H3K9me2-dependent transcriptional responses","volume":"6","author":"Sugeno","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8465","DOI":"10.1021\/bi0341152","article-title":"Nuclear localization of alpha-synuclein and its interaction with histones","volume":"42","author":"Goers","year":"2003","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15685","DOI":"10.1002\/chem.201803933","article-title":"Alpha-Synuclein Modulates the Physical Properties of DNA","volume":"24","author":"Jiang","year":"2018","journal-title":"Chemistry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13024-018-0241-0","article-title":"Extracellular alpha-synuclein levels are regulated by neuronal activity","volume":"13","author":"Yamada","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1038\/ncomms2534","article-title":"Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia","volume":"4","author":"Kim","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9595","DOI":"10.1074\/jbc.M411805200","article-title":"Structure and dynamics of micelle-bound human alpha-synuclein","volume":"280","author":"Ulmer","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","article-title":"Staging of brain pathology related to sporadic Parkinson\u2019s disease","volume":"24","author":"Braak","year":"2003","journal-title":"Neurobiol. Aging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nm1747","article-title":"Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson\u2019s disease","volume":"14","author":"Kordower","year":"2008","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.neuron.2019.05.035","article-title":"Transneuronal Propagation of Pathologic alpha-Synuclein from the Gut to the Brain Models Parkinson\u2019s Disease","volume":"103","author":"Kim","year":"2019","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S281","DOI":"10.3233\/JPD-191721","article-title":"Brain-First versus Gut-First Parkinson\u2019s Disease: A Hypothesis","volume":"9","author":"Borghammer","year":"2019","journal-title":"J. Parkinsons Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/mds.27556","article-title":"Gut-brain axis and the spread of alpha-synuclein pathology: Vagal highway or dead end?","volume":"34","author":"Breen","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"573696","DOI":"10.3389\/fcell.2020.573696","article-title":"Alpha Synuclein Connects the Gut-Brain Axis in Parkinson\u2019s Disease Patients\u2014A View on Clinical Aspects, Cellular Pathology and Analytical Methodology","volume":"8","author":"Schaeffer","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/NEN.0b013e318217d95f","article-title":"Transmission of prion strains in a transgenic mouse model overexpressing human A53T mutated alpha-synuclein","volume":"70","author":"Mougenot","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1093\/brain\/awt037","article-title":"Prion-like spreading of pathological alpha-synuclein in brain","volume":"136","author":"Nonaka","year":"2013","journal-title":"Brain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3389\/fnmol.2014.00042","article-title":"Protein phosphorylation in neurodegeneration: Friend or foe?","volume":"7","author":"Tenreiro","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-94-007-5416-4_6","article-title":"\u03b1-Synuclein aggregation and modulating factors","volume":"65","author":"Paleologou","year":"2012","journal-title":"Subcell. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0079-6123(10)83007-9","article-title":"Role of post-translational modifications in modulating the structure, function and toxicity of alpha-synuclein: Implications for Parkinson\u2019s disease pathogenesis and therapies","volume":"183","author":"Oueslati","year":"2010","journal-title":"Prog. Brain Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"49071","DOI":"10.1074\/jbc.M208046200","article-title":"Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions","volume":"277","author":"Hasegawa","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/ncb748","article-title":"alpha-Synuclein is phosphorylated in synucleinopathy lesions","volume":"4","author":"Fujiwara","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.neuroscience.2011.10.042","article-title":"alpha-synuclein phosphorylation and truncation are normal events in the adult human brain","volume":"200","author":"Muntane","year":"2012","journal-title":"Neuroscience"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1074\/jbc.275.1.390","article-title":"Constitutive phosphorylation of the Parkinson\u2019s disease associated alpha-synuclein","volume":"275","author":"Okochi","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1749-6632.2000.tb06902.x","article-title":"Physiology and pathophysiology of alpha-synuclein. Cell culture and transgenic animal models based on a Parkinson\u2019s disease-associated protein","volume":"920","author":"Kahle","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"29739","DOI":"10.1074\/jbc.M600933200","article-title":"Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease","volume":"281","author":"Anderson","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1172\/JCI200215777","article-title":"Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies","volume":"110","author":"Neumann","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0304-3940(02)01258-2","article-title":"Phosphorylation of alpha-synuclein characteristic of synucleinopathy lesions is recapitulated in alpha-synuclein transgenic Drosophila","volume":"336","author":"Takahashi","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1111\/j.1471-4159.2004.02728.x","article-title":"Overexpression of alpha-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of alpha-synuclein and activation of caspase-9: Resemblance to pathogenetic changes in Parkinson\u2019s disease","volume":"91","author":"Yamada","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/nn1443","article-title":"Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease","volume":"8","author":"Chen","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Xu, J., Kawahata, I., Izumi, H., and Fukunaga, K. (2021). T-Type Ca(2+) Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126185"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"12786","DOI":"10.1021\/ja0726613","article-title":"Paramagnetism-based NMR restraints provide maximum allowed probabilities for the different conformations of partially independent protein domains","volume":"129","author":"Bertini","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1006\/jmbi.2001.4538","article-title":"Conformational properties of alpha-synuclein in its free and lipid-associated states","volume":"307","author":"Eliezer","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"15477","DOI":"10.1073\/pnas.0507405102","article-title":"Structure and properties of alpha-synuclein and other amyloids determined at the amino acid level","volume":"102","author":"Greenbaum","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"26515","DOI":"10.1074\/jbc.M003542200","article-title":"Synucleins are a novel class of substrates for G protein-coupled receptor kinases","volume":"275","author":"Pronin","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"9227","DOI":"10.1523\/JNEUROSCI.0341-06.2006","article-title":"The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson\u2019s disease","volume":"26","author":"Arawaka","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Wu, W., Sung, C.C., Yu, P., Li, J., and Chung, K.K.K. (2020). S-Nitrosylation of G protein-coupled receptor kinase 6 and Casein kinase 2 alpha modulates their kinase activity toward alpha-synuclein phosphorylation in an animal model of Parkinson\u2019s disease. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0235296"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4711","DOI":"10.1016\/j.febslet.2007.08.067","article-title":"Casein kinase 2 is the major enzyme in brain that phosphorylates Ser129 of human alpha-synuclein: Implication for alpha-synucleinopathies","volume":"581","author":"Ishii","year":"2007","journal-title":"FEBS Lett."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s40478-021-01281-9","article-title":"Tyrosine 136 phosphorylation of \u03b1-synuclein aggregates in the Lewy body dementia brain: Involvement of serine 129 phosphorylation by casein kinase 2","volume":"9","author":"Sano","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1074\/jbc.C800206200","article-title":"Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system","volume":"284","author":"Inglis","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1074\/jbc.M109.081950","article-title":"Phosphorylation of synucleins by members of the Polo-like kinase family","volume":"285","author":"Mbefo","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.neuroscience.2013.09.061","article-title":"In Vivo modulation of polo-like kinases supports a key role for PLK2 in Ser129 \u03b1-synuclein phosphorylation in mouse brain","volume":"256","author":"Bergeron","year":"2014","journal-title":"Neuroscience"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.bbrc.2009.06.142","article-title":"Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications","volume":"387","author":"Qing","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.bbrc.2009.10.126","article-title":"Lrrk2 interaction with alpha-synuclein in diffuse Lewy body disease","volume":"390","author":"Qing","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","article-title":"Parkinson\u2019s disease","volume":"386","author":"Kalia","year":"2015","journal-title":"Lancet"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"N\u00fcbling, G.S., Levin, J., Bader, B., Lorenzl, S., Hillmer, A., H\u00f6gen, T., Kamp, F., and Giese, A. (2014). Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098906"},{"key":"ref_66","first-page":"392180","article-title":"Contribution of Alanine-76 and Serine Phosphorylation in \u03b1-Synuclein Membrane Association and Aggregation in Yeasts","volume":"2011","author":"Fiske","year":"2011","journal-title":"Parkinsons Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"7098","DOI":"10.1074\/jbc.M111.237131","article-title":"Phosphorylation of \u03b1-synuclein protein at Ser-129 reduces neuronal dysfunction by lowering its membrane binding property in Caenorhabditis elegans","volume":"287","author":"Kuwahara","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s40478-019-0696-4","article-title":"Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration","volume":"7","author":"Wang","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_69","first-page":"342ra378","article-title":"alpha-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson\u2019s disease","volume":"8","author":"Barrett","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jns.2007.08.027","article-title":"Localization of CKII beta subunits in Lewy bodies of Parkinson\u2019s disease","volume":"266","author":"Ryu","year":"2008","journal-title":"J. Neurol. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.4161\/cc.10.14.16494","article-title":"From Plk1 to Plk5: Functional evolution of polo-like kinases","volume":"10","author":"Manning","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.advenzreg.2008.04.002","article-title":"Protein kinase CK2\u2014A key suppressor of apoptosis","volume":"48","author":"Ahmad","year":"2008","journal-title":"Adv. Enzym. Regul."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3090","DOI":"10.1523\/JNEUROSCI.22-08-03090.2002","article-title":"A role for alpha-synuclein in the regulation of dopamine biosynthesis","volume":"22","author":"Perez","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"17648","DOI":"10.1074\/jbc.M110.100867","article-title":"Serine 129 phosphorylation reduces the ability of alpha-synuclein to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo","volume":"285","author":"Lou","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1007\/s00702-009-0304-z","article-title":"Accumulation of phosphorylated tyrosine hydroxylase into insoluble protein aggregates by inhibition of an ubiquitin-proteasome system in PC12D cells","volume":"116","author":"Kawahata","year":"2009","journal-title":"J. Neural Transm."},{"key":"ref_76","first-page":"1","article-title":"Immunohistochemical analyses of the postmortem human brains from patients with Parkinson\u2019s disease with anti-tyrosine hydroxylase antibodies","volume":"23","author":"Kawahata","year":"2009","journal-title":"Biog. Amines"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.bbrc.2015.07.125","article-title":"Dopamine or biopterin deficiency potentiates phosphorylation at (40)Ser and ubiquitination of tyrosine hydroxylase to be degraded by the ubiquitin proteasome system","volume":"465","author":"Kawahata","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Kawahata, I., and Fukunaga, K. (2020). Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson\u2019s Disease and Dopa-Responsive Dystonia. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113779"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.neuron.2004.10.023","article-title":"Cloning of the gene containing mutations that cause PARK8-linked Parkinson\u2019s disease","volume":"44","author":"Jain","year":"2004","journal-title":"Neuron"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.neuron.2004.11.005","article-title":"Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology","volume":"44","author":"Zimprich","year":"2004","journal-title":"Neuron"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1002\/ana.20484","article-title":"An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family","volume":"57","author":"Funayama","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.neulet.2007.02.086","article-title":"Independent occurrence of I2020T mutation in the kinase domain of the leucine rich repeat kinase 2 gene in Japanese and German Parkinson\u2019s disease families","volume":"417","author":"Ohta","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s00109-012-0984-y","article-title":"LRRK2 interactions with \u03b1-synuclein in Parkinson\u2019s disease brains and in cell models","volume":"91","author":"Guerreiro","year":"2013","journal-title":"J. Mol. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.neuron.2011.08.033","article-title":"Exogenous \u03b1-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death","volume":"72","author":"Luk","year":"2011","journal-title":"Neuron"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"20051","DOI":"10.1073\/pnas.0908005106","article-title":"Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells","volume":"106","author":"Luk","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1093\/embo-reports\/kvf109","article-title":"Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes","volume":"3","author":"Kahle","year":"2002","journal-title":"EMBO Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1016\/j.neurobiolaging.2006.06.013","article-title":"Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice","volume":"28","author":"Freichel","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1093\/hmg\/ddi396","article-title":"Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity","volume":"14","author":"Smith","year":"2005","journal-title":"Hum. Mol. Genet"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1111\/j.1460-9568.2007.05736.x","article-title":"Oxidative stress-induced phosphorylation, degradation and aggregation of alpha-synuclein are linked to upregulated CK2 and cathepsin D","volume":"26","author":"Takahashi","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1073\/pnas.0711053105","article-title":"The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease","volume":"105","author":"Gorbatyuk","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.acthis.2009.07.007","article-title":"Phosphorylation of \u03b1-synuclein upregulates tyrosine hydroxylase activity in MN9D cells","volume":"113","author":"Wu","year":"2011","journal-title":"Acta Histochem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"10211","DOI":"10.1074\/jbc.M809671200","article-title":"Alpha-synuclein aggregation and Ser-129 phosphorylation-dependent cell death in oligodendroglial cells","volume":"284","author":"Kragh","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"16895","DOI":"10.1074\/jbc.M800747200","article-title":"Phosphorylation at Ser-129 but not the phosphomimics S129E\/D inhibits the fibrillation of alpha-synuclein","volume":"283","author":"Paleologou","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/jnr.22537","article-title":"Characterization of kinases involved in the phosphorylation of aggregated \u03b1-synuclein","volume":"89","author":"Waxman","year":"2011","journal-title":"J. Neurosci. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1093\/hmg\/dds058","article-title":"Suppression of \u03b1-synuclein toxicity and vesicle trafficking defects by phosphorylation at S129 in yeast depends on genetic context","volume":"21","author":"Sancenon","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_96","first-page":"872","article-title":"Phosphorylation does not prompt, nor prevent, the formation of alpha-synuclein toxic species in a rat model of Parkinson\u2019s disease","volume":"18","author":"Schneider","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.3390\/ijms15011040","article-title":"In Vitro Phosphorylation Does not Influence the Aggregation Kinetics of WT \u03b1-Synuclein in Contrast to Its Phosphorylation Mutants","volume":"15","author":"Schreurs","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"105291","DOI":"10.1016\/j.nbd.2021.105291","article-title":"In Vivo aggregation of presynaptic alpha-synuclein is not influenced by its phosphorylation at serine-129","volume":"152","author":"Weston","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"106736","DOI":"10.1016\/j.bpc.2021.106736","article-title":"Intermediates of alpha-synuclein aggregation: Implications in Parkinson\u2019s disease pathogenesis","volume":"281","author":"Gadhe","year":"2022","journal-title":"Biophys. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1007\/s11064-009-9986-8","article-title":"Modulation of alpha-synuclein aggregation by dopamine: A review","volume":"34","author":"Leong","year":"2009","journal-title":"Neurochem. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.expneurol.2012.11.020","article-title":"Changes in properties of serine 129 phosphorylated alpha-synuclein with progression of Lewy-type histopathology in human brains","volume":"240","author":"Walker","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s00401-009-0538-8","article-title":"Unified staging system for Lewy body disorders: Correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction","volume":"117","author":"Beach","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s00401-011-0815-1","article-title":"Changes in the solubility and phosphorylation of alpha-synuclein over the course of Parkinson\u2019s disease","volume":"121","author":"Zhou","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s12031-013-0030-8","article-title":"Pramipexole reduces phosphorylation of \u03b1-synuclein at serine-129","volume":"51","author":"Chau","year":"2013","journal-title":"J. Mol. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"5827","DOI":"10.1038\/ncomms6827","article-title":"Phosphorylation of LRRK2 by casein kinase 1alpha regulates trans-Golgi clustering via differential interaction with ARHGEF7","volume":"5","author":"Chia","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.freeradbiomed.2014.05.022","article-title":"Polo-like kinase 2 activates an antioxidant pathway to promote the survival of cells with mitochondrial dysfunction","volume":"73","author":"Li","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"100273","DOI":"10.1016\/j.jbc.2021.100273","article-title":"Genetic deletion of Polo-like kinase 2 reduces alpha-synuclein serine-129 phosphorylation in presynaptic terminals but not Lewy bodies","volume":"296","author":"Weston","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1016\/j.bmcl.2013.02.065","article-title":"Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors","volume":"23","author":"Bowers","year":"2013","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1002\/cmdc.201300166","article-title":"Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce alpha-synuclein phosphorylation in rat brain","volume":"8","author":"Aubele","year":"2013","journal-title":"Chem. Med. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Elfarrash, S., Jensen, N.M., Ferreira, N., Schmidt, S.I., Gregersen, E., Vestergaard, M.V., Nabavi, S., Meyer, M., and Jensen, P.H. (2021). Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein but not of the aggregated alpha-synuclein. PLoS ONE, 16.","DOI":"10.1101\/2021.05.21.445104"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"4127","DOI":"10.1096\/fj.10-179192","article-title":"Phosphorylated \u03b1-synuclein can be detected in blood plasma and is potentially a useful biomarker for Parkinson\u2019s disease","volume":"25","author":"Foulds","year":"2011","journal-title":"FASEB J."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1038\/srep02540","article-title":"A longitudinal study on \u03b1-synuclein in blood plasma as a biomarker for Parkinson\u2019s disease","volume":"3","author":"Foulds","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.expneurol.2006.12.006","article-title":"Plasma alpha-synuclein is decreased in subjects with Parkinson\u2019s disease","volume":"204","author":"Li","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Ishii, R., Tokuda, T., Tatebe, H., Ohmichi, T., Kasai, T., Nakagawa, M., Mizuno, T., and El-Agnaf, O.M. (2015). Decrease in plasma levels of alpha-synuclein is evident in patients with Parkinson\u2019s disease after elimination of heterophilic antibody interference. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0123162"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/mds.22928","article-title":"Plasma alpha-synuclein in patients with Parkinson\u2019s disease with and without treatment","volume":"25","author":"Duran","year":"2010","journal-title":"Mov. Disord."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.3389\/fneur.2019.01388","article-title":"Plasma and Serum Alpha-Synuclein as a Biomarker of Diagnosis in Patients With Parkinson\u2019s Disease","volume":"10","author":"Chang","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1002\/acn3.729","article-title":"Plasma alpha-synuclein detected by single molecule array is increased in PD","volume":"6","author":"Ng","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s00401-014-1284-0","article-title":"Cutaneous neuropathy in Parkinson\u2019s disease: A window into brain pathology","volume":"128","author":"Doppler","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1212\/WNL.0000000000000316","article-title":"Skin nerve \u03b1-synuclein deposits: A biomarker for idiopathic Parkinson disease","volume":"82","author":"Donadio","year":"2014","journal-title":"Neurology"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1002\/mds.24993","article-title":"Lewy pathology in gastric and duodenal biopsies in Parkinson\u2019s Disease","volume":"27","author":"Pouclet","year":"2012","journal-title":"Mov. Disord."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s00401-013-1214-6","article-title":"Accumulation of \u03b1-synuclein in the bowel of patients in the pre-clinical phase of Parkinson\u2019s disease","volume":"127","author":"Hilton","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s40478-017-0456-2","article-title":"The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson\u2019s disease","volume":"5","author":"Finkelstein","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3233\/JPD-212877","article-title":"The Compound ATH434 Prevents Alpha-Synuclein Toxicity in a Murine Model of Multiple System Atrophy","volume":"12","author":"Finkelstein","year":"2022","journal-title":"J. Parkinsons Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/6216\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:23:28Z","timestamp":1760138608000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/6216"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,1]]},"references-count":123,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23116216"],"URL":"https:\/\/doi.org\/10.3390\/ijms23116216","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,1]]}}}