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Human Molecular Genetics Advance Access originally published online on August 19, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 20 2625-2635
DOI: 10.1093/hmg/ddg283
© 2003 Oxford University Press

Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies

Atsushi Iwata1,2, Mieko Maruyama1, Takumi Akagi3, Tsutomu Hashikawa3, Ichiro Kanazawa4, Shoji Tsuji2 and Nobuyuki Nukina1,*

1Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa Wako-shi, Saitama 351-0198, Japan, 2Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo Bunkyo-ku, Tokyo 113-8655, Japan, 3Laboratory for Neural Architecture, RIKEN Brain Science Institute, 2-1 Hirosawa Wako-shi, Saitama 351-0198, Japan and 4National Center for Psychiatry and Neurology, 4-1-1 Ogawahigashi-cho Kodaira-shi, Tokyo 187-8551, Japan

Received June 2, 2003; Revised July 31, 2003; Accepted August 13, 2003

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.

* To whom correspondence should be addressed. Email: nukina{at}brain.riken.go.jp


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