Exp Neurobiol.  2020 Jun;29(3):207-218. 10.5607/en20014.

Death-associated Protein Kinase 1 Phosphorylates α-Synuclein at Ser129 and Exacerbates Rotenone-induced Toxic Aggregation of α-Synuclein in Dopaminergic SH-SY5Y Cells

  • 1Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea


The formation of Lewy bodies (LBs), intracellular filamentous inclusions, is one of the hallmarks of Parkinson's disease (PD). α-Synuclein is the main component of LBs and its abnormal accumulation contributes to the pathogenesis of PD. Direct phosphorylation of α-synuclein at multiple Ser/Tyr residues is known to induce its aggregation, consequently promoting LB formation. Death-associated protein kinase 1 (DAPK1), originally identified as a positive mediator of γ-interferon-induced programmed cell death, possesses tumor-suppressive activity and mediates a wide range of cellular processes, including apoptosis and autophagy. Accumulating evidence suggests that DAPK1 is also associated with neuronal cell death and neurodegeneration. For example, DAPK1 phosphorylates tau and amyloid precursor protein, and induces tau aggregation and amyloid β production, respectively, in Alzheimer’s disease. DAPK1 is also accumulated to a larger extent in a mouse model of PD, causing synucleinopathy and dopaminergic neuron degeneration. In this study, we attempted to determine whether DAPK1 phosphorylates α-synuclein and affects cell viability in human dopaminergic neuroblastoma SH-SY5Y cells. We demonstrated that DAPK1 directly phosphorylates α-synuclein at Ser129, and induces the formation of insoluble α-synuclein aggregates. We also showed that DAPK1 enhances rotenone-induced aggregation of α-synuclein, potentiating neuronal cell death. Taken together, these findings suggest that DAPK1 acts as a novel regulator of toxic α-synuclein aggregation, possibly affecting and playing a role in the development of PD.


Death-associated protein kinase 1; α-Synuclein; Parkinson’s disease; Phosphorylation; Protein aggregation
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