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.
Mesh Terms:
Animals, Brain, Cell Line, Cytoplasm, Cytosol, DNA, Complementary, Dose-Response Relationship, Drug, Down-Regulation, Gene Library, Humans, Image Processing, Computer-Assisted, Kallikreins, Mice, Mice, Inbred C57BL, Mitochondria, Nerve Tissue Proteins, Parkinson Disease, Polymers, Precipitin Tests, Protein Binding, RNA Interference, RNA, Small Interfering, Serine Endopeptidases, Subcellular Fractions, Synucleins, alpha-Synuclein
Hum. Mol. Genet.
Date: Oct. 15, 2003
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