title: α-Synuclein phosphorylation as a therapeutic target in Parkinson's disease.
abstract: Phosphorylation is a key post-translational modification necessary for normal cellular signaling and, therefore, lies at the heart of cellular function. In neurodegenerative disorders, abnormal hyperphosphorylation of pathogenic proteins is a common phenomenon that contributes in important ways to the disease process. A prototypical protein that is hyperphosphorylated in the brain is α-synuclein (α-syn) - found in Lewy bodies and Lewy neurites - the pathological hallmarks of Parkinson's disease (PD) and other α-synucleinopathies. The genetic linkage of α-syn to PD as well as its pathological association in both genetic and sporadic cases have made it the primary protein of interest. In understanding how α-syn dysfunction occurs, increasing focus is being placed on its abnormal aggregation and the contribution of phosphorylation to this process. Studies of both the kinases and phosphatases that regulate α-syn phosphorylation are beginning to reveal the roles of this post-translational modification in disease pathogenesis. Modulation of α-syn phosphorylation may ultimately prove to be a viable strategy for disease-modifying therapeutic interventions. In this review, we explore mechanisms related to α-syn phosphorylation, its biophysical and functional consequences, and its role in neurodegeneration.
authors.affiliation: Signum Biosciences Inc., 7 Deer Park Drive, Suite H, Monmouth Junction, NJ 08852, USA. sbraithwaite@signumbio.com
authors.forename: Steven P
authors.initials: SP
authors.lastname: Braithwaite
authors.forename: Jeffry B
authors.initials: JB
authors.lastname: Stock
authors.forename: M Maral
authors.initials: MM
authors.lastname: Mouradian
mesh_terms: D000818:Animals; D047389:Casein Kinase I / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004330:Drosophila; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016631:Lewy Bodies / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D012694:Serine / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D047389:Casein Kinase I; D047390:Casein Kinase II; D018797:Cell Cycle Proteins; D054768:G-Protein-Coupled Receptor Kinases; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010749:Phosphoprotein Phosphatases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012694:Serine; D051844:alpha-Synuclein; D000097869:Polo-Like Kinase 1; C495280:LRRK2 protein, human