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

Abstract

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.

Effects of gender on nigral gene expression and parkinson disease

“…This approach revealed that genes affected by disease but not gender were involved several cellular processes such as transmission of nerve impulse, synaptic transmission, cell-cell signaling, establishment of localization, localization, transport (Fig 3). Among the genes that exhibit gender-independent altered expression in PD are: neuronal beta-catenin, which has been implicated in Alzheimer disease and synaptic plasticity (Fuentealba et al, 2004;Goda, 2002); PAEL-R, a protein accumulated in Lewy bodies (Murakami et al, 2004) and a potential parkin substrate (Nakahara et al, 2003;Yang et al, 2003); kallikrein 6, involved in ASYN degradation (Iwata et al, 2003); and transferrin, which may be related to iron deposition observed in PD brain (Morris et al, 1994).…”

Stabilization of α-Synuclein Protein with Aging and Familial Parkinson's Disease-Linked A53T Mutation

“…Currently, the actual protease system(s) responsible for the cellular metabolism of ␣-Syn is unknown; however, a number of proteolytic systems are implicated in the cellular metabolism of ␣-Syn, including proteasomes (Bennett et al, 1999;Tofaris et al, 2001;Webb et al, 2003), lysosomes-autophagy (Paxinou et al, 2001;Webb et al, 2003), calpains (Mishizen-Eberz et al, 2003), and kallikrins (Iwata et al, 2003). Because aging is associated with decreases in the activity of these proteases (Goto et al, 2001;Gozal et al, 2003;Li et al, 2004), it is tempting to hypothesize that increases in the stability of ␣-Syn with aging could result from the decline in lysosomal and proteasomal activity.…”

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

“…Proteolytic clearance is possible using any of several proteases that have been identified to be able to cleave and degrade α-syn: these include neurosin, 55 matrix metalloproteinases (MMPs), 56 calpain, 57 cathepsin D 58 and plasmin. 59 Among them, neurosin, MMPs and plasmin have been reported to cleave and degrade extracellular α-syn.…”

“…Neurosin, a serine protease, is preferentially expressed in neurons and oligodendrocytes in the brain. 55 It was first observed to be colocalized in some senile plaques in AD patients as well as Lewy bodies in PD patients. 60 It has also been reported to degrade intracellular α-syn, but less efficiently A53T α-syn and also to inhibit α-syn polymerization.…”

“…60 It has also been reported to degrade intracellular α-syn, but less efficiently A53T α-syn and also to inhibit α-syn polymerization. 55 Tatebe et al later demonstrated in vitro that secreted neurosin degrades extracellular α-syn. 61 Recently, the viral mediated delivery of neurosin has been shown to promote the clearance of α-syn and reduces pathology in an α-syn model, 62 implying that neurosin may be a new therapeutic target for PD.…”