Cleavage of normal and pathological forms of α-synuclein by neurosin in vitro

Kasai, Takashi; Tokuda, Takahiko; Yamaguchi, Naohito; Watanabe, Yoshihisa; Kametani, Fuyuki; Nakagawa, Masanori; Mizuno, Toshiki

doi:10.1016/j.neulet.2008.02.057

Cited by 62 publications

(81 citation statements)

References 29 publications

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“…MMP-3 has been reported to cleave T54, E57, A78, Q79, A91, and G93 within the ␣-syn sequence (34) while neurosin cleaves K80, K97, E114, and D121 sequence (60). On the contrary, plasmin cleaves ␣-syn from its N-terminal region and subsequently amino acids below the lysine residue within ␣-syn sequence (K10, K32, K43, K58, K80, and K97) specifically (Fig.…”

Section: Discussionmentioning

confidence: 99%

Proteolytic Cleavage of Extracellular α-Synuclein by Plasmin

Kim

Choi

Park

et al. 2012

Journal of Biological Chemistry

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Background: A prion-like spread of ␣-synuclein might play a role in the pathogenesis of Parkinson disease. Results: Extracellular ␣-synuclein was cleaved by plasmin. Cultured microglia and astrocytes did not take up plasmin digested extracellular ␣-synuclein, and were not activated. Conclusion: Plasmin-mediated ␣-synuclein clearance problems might play a role in the pathogenesis of Parkinson disease. Significance: Therapies aimed at ␣-synuclein clearance may lead to new therapies for Parkinson disease.

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Section: Discussionmentioning

confidence: 99%

Proteolytic Cleavage of Extracellular α-Synuclein by Plasmin

Kim

Choi

Park

et al. 2012

Journal of Biological Chemistry

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“…This observation led us to believe that intracellular interaction of active MMP3 with ␣-synuclein, probably cleaving ␣-synuclein, is possible. Serine protease neurosin also can cleave ␣-synuclein and co-localize with LB (16,17). A number of studies suggests that inclusion body formation is a part of cellular protection mechanism by reducing diffuse distribution of toxic molecules (34,35).…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports showed that matrix metalloproteinases were able to cleave ␣-synuclein, and MMP3 was the most efficient enzyme among them in cleaving ␣-synuclein into several fragments (14). Several other proteinases that include calpain, neurosin, and proteasome 20 S are known to cleave ␣-synuclein in DA neurons and are localized in or around LB where ␣-synuclein is localized (10,(15)(16)(17)(18). However, the role of cleaved peptides is still obscure.…”

mentioning

confidence: 99%

Role of Matrix Metalloproteinase 3-mediated α-Synuclein Cleavage in Dopaminergic Cell Death

Choi

Kim

et al. 2011

Journal of Biological Chemistry

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Evidence suggests that the C-terminal truncation of ␣-synuclein is equally important as aggregation of ␣-synuclein in Parkinson disease (PD). Our previous results showed that an endopeptidase, matrix metalloproteinase-3 (MMP3), was induced and activated in dopaminergic (DA) cells upon stress conditions. Here, we report that MMP3 cleaved ␣-synuclein in vitro and in vivo and that ␣-synuclein and MMP3 were co-localized in Lewy bodies (LB) in the postmortem brains of PD patients. Incubation of ␣-synuclein with the catalytic domain of MMP3 (cMMP3) resulted in generation of several peptides, and the peptide profiles of WT ␣-synuclein (WTsyn) and A53T mutant (A53Tsyn) were different. Combined analysis using mass spectrometry and N-terminal determination revealed that MMP3 generated C-terminally truncated peptides of amino acids 1-78, 1-91, and 1-93 and that A53Tsyn produced significantly higher quantities of these peptides. Similar sizes of peptides were detected in N27 DA cells under oxidative stress and RNA interference to knock down MMP3-attenuated peptide generation. Co-overexpression of cMMP3 with either WTsyn or A53Tsyn led to a reduction in Triton X-100-insoluble aggregates and an increase in protofibril-like small aggregates. In addition, overexpression of the 1-93-amino acid peptide in the substantia nigra led to DA neuronal loss without LB-like aggregate formation. The results strongly indicate that MMP3 digestion of ␣-synuclein in DA neurons plays a pivotal role in the progression of PD through modulation of ␣-synuclein in aggregation, LB formation, and neurotoxicity.The epidemiological as well as animal studies suggest that environmental factors, genetic predispositions, and the interplay between the two factors are implicated in the PD 3 pathogenesis (1), although the underlying molecular mechanisms remain largely unknown. ␣-Synuclein is a major component of Lewy bodies (LB), the pathological hallmark of Parkinson disease (2). As expression of three mutant forms of ␣-synuclein, A53T, A30P, and E46K, in the brain (3-5) and increased copy number by duplication or triplication of the wild-type ␣-synuclein gene (6 -8) have been reported in the early onset familial cases of PD, the pathophysiological role of these mutants of ␣-synuclein has been a target of extensive investigations in PD research. The ability of ␣-synuclein to aggregate and form fibrillar deposits has been shown to play a central role in its pathology. The facts that the presence of C-terminally truncated ␣-synuclein in LB of sporadic PD and LB dementia (9, 10), the existence of various lengths of the truncated forms of ␣-synuclein in brain (10, 11), and the formation of C-terminally truncated ␣-synuclein in A53T transgenic mice that show motor symptoms (12) implicate the probable involvement of endopeptidases in cleaving ␣-synuclein in brains. In addition, about 15% of ␣-synuclein in LB are truncated forms, and incomplete degradation of ␣-synuclein produced highly amyloidogenic fragments (9, 13). Recent reports showed that matrix metalloprotei...

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“…Neurosin, a trypsin-like serine protease, was detected in LBs (Iwata et al, 2003;Ogawa et al, 2000). The in vitro cleavage of a-syn by neurosin generates one major fragment 1-80, which does not aggre gate in vitro (Iwata et al, 2003) and three minor ones: 1-97, 1-114 and 1-121 (Kasai et al, 2008) (Fig. 5).…”

Section: Several Enzymes Have Been Implicated In the Proteolysis Of Amentioning

confidence: 99%

“…5). Interestingly, the phosphorylated form (S129-P) and the disease-associated mutants (A30P and A53T) are more resistant to proteoly sis by neurosin (Kasai et al, 2008).…”

Section: Several Enzymes Have Been Implicated In the Proteolysis Of Amentioning

confidence: 99%

Role of post-translational modifications in modulating the structure, function and toxicity of α-synuclein

Oueslati

Fournier

Lashuel

2010

Progress in Brain Research

315

278

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A better understanding of the molecular and cellular determinants that influence the pathology of Parkinson's disease (PD) is essential for developing effective diagnostic, preventative and therapeutic strategies to treat this devastating disease. A number of post-translational modifications to a-syn are present within the Lewy bodies in the brains of affected patients and transgenic models of PD and related disorders. However, whether disease-associated a-syn post-translational modifications promote or inhibit a-syn aggregation and neurotoxicity in vivo remains unknown. Herein, we summarize and discuss the major disease-associated post-translational modifications (phosphorylation, truncation and ubiquitination) and present our current understanding of the effect of these modifications on a-syn aggregation and toxicity. Elucidating the molecular mechanisms underlying post-translation modifications of a-syn and the consequences of such modifications on the biochemical, structural, aggregation and toxic properties of the protein is essential for unravelling the molecular basis of its function(s) in health and disease. Furthermore, the identification of the natural enzymes involved in regulating the post-translational modifications of a-synuclein will yield novel and more tractable therapeutic targets to treat PD and related synucleinopathies.

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Cleavage of normal and pathological forms of α-synuclein by neurosin in vitro

Cited by 62 publications

References 29 publications

Proteolytic Cleavage of Extracellular α-Synuclein by Plasmin

Proteolytic Cleavage of Extracellular α-Synuclein by Plasmin

Role of Matrix Metalloproteinase 3-mediated α-Synuclein Cleavage in Dopaminergic Cell Death

Role of post-translational modifications in modulating the structure, function and toxicity of α-synuclein

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