Relationship between alpha synuclein phosphorylation, proteasomal inhibition and cell death: relevance to Parkinson’s disease pathogenesis

• Published in: Journal of neurochemistry Vol. 110; no. 3; pp. 1005 - 1013
• Main Authors: Chau, Kai‐Yin, Ching, Hey Long, Schapira, Anthony H. V., Cooper, J. Mark
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-08-2009; Wiley-Blackwell
• Subjects: alpha-Synuclein - adverse effects; alpha-Synuclein - biosynthesis; alpha-Synuclein - metabolism; Biochemistry; Biological and medical sciences; Cell Death - physiology; Cell Line, Tumor; Cellular biology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Humans; Kinases; Medical sciences; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Parkinson Disease - etiology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; phosphorylation; Phosphorylation - physiology; proteasomal inhibition; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors; Up-Regulation; α‐synuclein; Oxidative stress; Nervous system diseases; Phosphorylation; Parkinson's disease; Pathogenesis; Toxicity; Parkinson disease; Protein; Cerebral disorder; Aggregation; proteasomal inhibition; Sensitivity; Sodium; Cell death; Central nervous system disease; Degenerative disease; α-synuclein; Extrapyramidal syndrome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06191.x

Alpha synuclein can be phosphorylated at serine129 (P‐S129), and the presence of highly phosphorylated α‐synuclein in Lewy bodies suggests changes to its phosphorylation status has an important pathological role. We demonstrate that the kinase(s) responsible for α‐synuclein S129 phosphorylation is constitutively active in SH‐SY5Y cells and involves casein kinase 2 activity. Increased oxidative stress or proteasomal inhibition caused significant elevation of P‐S129 α‐synuclein levels. Under these conditions, similar increases in P‐S129 α‐synuclein were found in both sodium dodecyl sulphate lysates and Triton extracts indicating the phosphorylated protein was soluble and did not lead to aggregation. The rate of S129 phosphorylation was increased in response to proteasomal inhibition indicating a higher activity of the relevant kinase. Cells expressing the phosphorylation mimic, S129D α‐synuclein increased cell death and enhanced sensitivity to epoxomycin exposure. Proteasomal inhibition markedly decreased S129D α‐synuclein turnover suggesting proteasomal inhibition leads to the accumulation of P‐S129 α‐synuclein through an increase in the kinase activity and a decrease in protein turnover resulting in increased cell death. We conclude that S129 phosphorylation is toxic to dopaminergic cells and both the levels of S129 phosphorylated protein and its toxicity are increased with proteasomal inhibition emphasising the interdependence of these pathways in Parkinson’s disease pathogenesis.