Cleavage of α-sunuclein by Neurosin (Kallikrein-6)

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Background : Neurosin (Kallikrein-6), one of the serine proteases predominantly expressed in the central nervous system, was reported to be possible to degrade α-synuclein, a key protein for Parkinson disease. However, cleavage site of α-synuclein by neurosin has not been detected. In this study, cleavage sites of α-synuclein were identified by LC/MS/MS.Method : Degradations of wild and mutant α-synuclein by neurosin were evaluated semi-quantitatively by SDS-PAGE. Restricted fragments of α-synuclein cleaved by neurosin were examined by LC/MS/MS (Ion trap mass spectrometer ; LCQ Advatage, Themo Electron Corporation, Waltham, MA).Results : The first cleaving site of α-synuclein was Lyn80, and secondly Lyn96, Lyn97, Asp115 and Asp121 were cleaved by neurosin. A30P mutant α-synuclein was degraded slower than wild α-synuclein by neurosin.Interpretation : The dominant cleaving site of Lyn80 is the center of the NAC region, which is responsible for polymerization of the α-synuclein. Our results showed that neurosin can degrade α-synuclein and it may inhibit the polymerization of α-synuclein by cleaving the NAC region.