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

Abstract

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.

Comparison of the effect of rotenone and 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine on inducing chronic Parkinson's disease in mouse models

“…Lewy bodies can activate surrounding microglia, promote the release of inflammatory mediators, and aggravate neuronal injury ( 38 ). A small fraction of α-synuclein is phosphorylated at the S129 site (<4%) in healthy brains, but it has been observed to be accumulated (~90%) in the brains of patients with PD ( 39 ). Therefore, pS129 α-synuclein was used as a marker to evaluate the pathological changes associated with α-synuclein.…”

Methanolic Extract of Boswellia serrata Gum Protects the Nigral Dopaminergic Neurons from Rotenone-Induced Neurotoxicity

“…These observations suggest that BDNF induction at least in part might contribute to the neuroprotective effects of Boswellia extract. These also highlight the pleiotropic actions of AMPK in Previous studies demonstrated that rotenone treatment elevated numbers of α-synuclein cytoplasmatic inclusions in neurons and α-synuclein phosphorylation [58][59][60]. A more direct link between apoptosis and DNA damage has been described in relation to α-synuclein.…”

“…Previous studies demonstrated that rotenone treatment elevated numbers of α-synuclein cytoplasmatic inclusions in neurons and α-synuclein phosphorylation [ 58 – 60 ]. A more direct link between apoptosis and DNA damage has been described in relation to α-synuclein.…”

Emerging Potential of Exosomal Non-coding RNA in Parkinson’s Disease: A Review

“…Mounting evidence has shown that EVs acts as a key mediator in the central nervous system communication that actively responds to nervoual damage, mediating inflammation and inflammation-related neuroprotection ( Delpech et al, 2019 ). Lewy body formation (LBs) is the underlying neuropathological feature of PD ( Shin and Chung, 2020 ), mainly composed of αlpha-synuclein. Under normal conditions, α-synuclein exists in a soluble form.…”