Proteolytic cleavage of extracellular secreted α-synuclein via matrix metalloproteinases

Jee Young Sung, Sung Min Park, Choong Hwan Lee, Ji Won Um, Hyun Jung Lee, Jongsun Kim, Young J. Oh, Seung Taek Lee, Seung R. Paik, Kwang Chul Chung

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169 Citations (Scopus)

Abstract

Although α-synuclein is the main structural component of the insoluble filaments that form Lewy bodies in Parkinson disease (PD), its physiological function and exact role in neuronal death remain poorly understood. In the present study, we examined the possible functional relationship between α-synuclein and several forms of matrix metalloproteinases (MMPs) in the human dopaminergic neuroblastoma (SK-N-BE) cell line. When SK-N-BE cells were transiently transfected with α-synuclein, it was secreted into the extracellular culture media, concomitantly with a significant decrease in cell viability. Also the addition of nitric oxide-generating compounds to the cells caused the secreted α-synuclein to be digested, producing a small fragment whose size was similar to that of the fragment generated during the incubation of α-synuclein with various MMPs in vitro. Among several forms of MMPs, α-synuclein was cleaved most efficiently by MMP-3, and MALDI-TOF mass spectra analysis showed that α-synuclein is cleaved from its C-terminal end with at least four cleavage sites within the non-Aβ component of AD amyloid sequence. Compared with the intact form, the protein aggregation of α-synuclein was remarkably facilitated in the presence of the proteolytic fragments, and the fragment-induced aggregates showed more toxic effect on cell viability. Moreover, the levels of MMP-3 were also found to be increased significantly in the rat PD brain model produced by the cerebral injection of 6-hydroxydopamine into the substantia nigra. The present study suggests that the extracellularly secreted α-synuclein could be processed via the activation of MMP-3 in a selective manner.

Original languageEnglish
Pages (from-to)25216-25224
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number26
DOIs
Publication statusPublished - 2005 Jul 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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