Oxidative stress-induced phosphorylation, degradation and aggregation of α-synuclein are linked to upregulated CK2 and cathepsin D

Makio Takahashi, Li Wen Ko, Jayanarayan Kulathingal, Peizhou Jiang, Daniel Sevlever, Shu Hui C. Yen

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Intracellular accumulation of α-synuclein (α-Syn) as filamentous aggregates is a pathological feature shared by Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, referred to as synucleinopathies. To understand the mechanisms underlying α-Syn aggregation, we established a tetracycline-off inducible transfectant (3D5) of neuronal lineage overexpressing human wild-type α-Syn. α-Syn aggregation was initiated by exposure of 3D5 cells to FeCl2. The exposure led to formation of α-Syn inclusions and oligomers of 34, 54, 68 kDa and higher molecular weights. The oligomers displayed immunoreactivity with antibodies to the amino-, but not to the carboxyl(C)-, terminus of α-Syn, indicating that C-terminally truncated α-Syn is a major component of oligomers. FeCl2 exposure also promoted accumulation of S129 phosphorylated monomeric α-Syn (Pα-Syn) and casein kinase 2 (CK2); however, G-protein-coupled receptor kinase 2 was reduced. Treatment of FeCl 2-exposed cells with CK2 inhibitors (DRB or TBB) led to decreased formation of α-Syn inclusions, oligomers and Pα-Syn. FeCl 2 exposure also enhanced the activity/level of cathepsin D. Treatment of the FeCl2-exposed cells with pepstatin A or NH4Cl led to reduced formation of oligomers/inclusions as well as of ∼ 10 and 12 kDa truncated α-Syn. Our results indicate that α-Syn phosphorylation caused by FeCl2 is due to CK2 upregulation, and that lysosomal proteases may have a role in producing truncated α-Syn for oligomer assembly.

Original languageEnglish (US)
Pages (from-to)863-874
Number of pages12
JournalEuropean Journal of Neuroscience
Volume26
Issue number4
DOIs
StatePublished - Aug 2007

Keywords

  • Casein kinase 2 (CK2)
  • Cathepsin D (CatD)
  • Oxidative stress
  • Phosphorylation
  • α-synuclein (α-Syn)

ASJC Scopus subject areas

  • Neuroscience(all)

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