Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease

被引：161

作者：

Zhang, Zhentao ^{[1
,2
]}

Kang, Seong Su ^{[2
]}

Liu, Xia ^{[2
]}

Ahn, Eun Hee ^{[2
]}

Zhang, Zhaohui ^{[1
]}

He, Li ^{[3
]}

Iuvone, P. Michael ^{[3
,4
]}

Duong, Duc M. ^{[5
,6
]}

Seyfried, Nicholas T. ^{[5
,6
]}

Benskey, Matthew J. ^{[7
,8
]}

Manfredsson, Fredric P. ^{[7
,8
]}

Jin, Lingjing ^{[9
]}

Sun, Yi E. ^{[9
]}

Wang, Jian-Zhi ^{[10
,11
]}

Ye, Keqiang ^{[2
]}

机构：

[1] Wuhan Univ, Dept Neurol, Renmin Hosp, Wuhan, Hubei, Peoples R China

[2] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA

[3] Emory Univ, Sch Med, Dept Ophthalmol, Atlanta, GA 30322 USA

[4] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA

[5] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA

[6] Emory Univ, Sch Med, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA

[7] Michigan State Univ, Coll Human Med, Translat Sci & Mol Med, Grand Rapids, MI USA

[8] Mercy Hlth St Marys, Hauenstein Neurosci Ctr, Grand Rapids, MI USA

[9] Tongji Univ, Sch Med, Translat Ctr Stem Cell Res, Tongji Hosp,Dept Regenerat Med, Shanghai, Peoples R China

[10] Huazhong Univ Sci & Technol, Tongji Med Coll, Pathophysiol Dept, Sch Basic Med, Wuhan, Hubei, Peoples R China

[11] Huazhong Univ Sci & Technol, Tongji Med Coll, Collaborat Innovat Ctr Brain Sci, Key Lab,Minist Educ China Neurol Disorders, Wuhan, Hubei, Peoples R China

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2017年 / 24卷 / 08期

关键词：

ALZHEIMERS-DISEASE; IN-VITRO; ANIMAL-MODELS; CATHEPSIN-D; AGGREGATION; DEGRADATION; PROTEIN; MICE; LEGUMAIN; MUTATION;

D O I：

10.1038/nsmb.3433

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Aggregated forms of alpha-synuclein play a crucial role in the pathogenesis of synucleinopathies such as Parkinson's disease (PD). However, the molecular mechanisms underlying the pathogenic effects of alpha-synuclein are not completely understood. Here we show that asparagine endopeptidase (AEP) cleaves human alpha-synuclein, triggers its aggregation and escalates its neurotoxicity, thus leading to dopaminergic neuronal loss and motor impairments in a mouse model. AEP is activated and cleaves human alpha-synuclein at N103 in an age-dependent manner. AEP is highly activated in human brains with PD, and it fragments alpha-synuclein, which is found aggregated in Lewy bodies. Overexpression of the AEP-cleaved alpha-synuclein(1-103) fragment in the substantia nigra induces both dopaminergic neuronal loss and movement defects in mice. In contrast, inhibition of AEP-mediated cleavage of alpha-synuclein (wild type and A53T mutant) diminishes alpha-synuclein's pathologic effects. Together, these findings support AEP's role as a key mediator of alpha-synuclein-related etiopathological effects in PD.

引用

页码：632 / +

页数：13

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