Identification of the amino acid sequence motif of alpha-synuclein responsible for macrophage activation.
Alpha-synuclein (Syn) is implicated in the pathogenesis of PD and related neurodegenerative disorders. Recent studies have also shown that alpha-synuclein can activate microglia and enhance dopaminergic neurodegeneration. The mechanisms of microglia activation by alpha-synuclein, however, are not well understood. In this study, we found that not only alpha-synuclein but also beta- and gamma-synucleins activated macrophages (RAW 264.7) in vitro. Macrophages treated with synuclein proteins secreted TNF-alpha in a dose-dependent manner. Synuclein family proteins also increased mRNA transcription of COX-2 and iNOS. Two alpha-synuclein deletion mutants, SynDeltaNAC and Syn61-140, activated macrophages, while deletion mutants Syn1-60 and Syn96-140 did not significantly activate them. Finally, we demonstrated that macrophage activation by alpha-synuclein was accompanied by phosphorylation of ERK. These results suggest that synuclein family proteins can activate macrophages, and that macrophage activation needs both the N-terminal and C-terminal domains of alpha-synuclein, but not the central NAC region.
Lee
Saet-byul
SB
Department of Microbiology and Brain Korea 21 Projects For Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Republic of Korea.
Park
Sang Myun
SM
Ahn
Keun Jae
KJ
Chung
Kwang Chul
KC
Paik
Seung R
SR
Kim
Jongsun
J
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D002460:Cell Line; D004252:DNA Mutational Analysis; D006801:Humans; D008262:Macrophage Activation / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020539:Sequence Analysis, Protein; D017384:Sequence Deletion; D051844:alpha-Synuclein / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
D011994:Recombinant Proteins; D051844:alpha-Synuclein