Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies.
Accumulation of insoluble alpha-synuclein aggregates in the brain is characteristic of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Although numerous studies on the aggregation properties of alpha-synuclein have been reported, little is known about its degradation so far. In view of proteolytic degradation, we have found that the serine protease neurosin (kallikrein-6) degrades alpha-synuclein and co-localizes with pathological inclusions such as Lewy bodies and glial cytoplasmic inclusions. In vitro study showed that neurosin prevented alpha-synuclein polymerization by reducing the amount of monomer and also by generating fragmented alpha-synucleins that themselves inhibited the polymerization. Upon cellular stress, neurosin was released from mitochondria to the cytosol, which resulted in the increase of degraded alpha-synuclein species. Down-regulation of neurosin caused accumulation of alpha-synuclein within cultured cells. Thus we concluded that neurosin plays a significant role in physiological alpha-synuclein degradation and also in the pathogenesis of synucleinopathies.
Iwata
Atsushi
A
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama, Japan.
Maruyama
Mieko
M
Akagi
Takumi
T
Hashikawa
Tsutomu
T
Kanazawa
Ichiro
I
Tsuji
Shoji
S
Nukina
Nobuyuki
N
D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015723:Gene Library; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007610:Kallikreins / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000473:pathology; D011108:Polymers / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D011108:Polymers; D034741:RNA, Small Interfering; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; C103551:KLK6 protein, human; D007610:Kallikreins; C491223:Prss18 protein, mouse; D012697:Serine Endopeptidases