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

Zhang, Zhentao; Kang, Seong Su; Liu, Xia; Ahn, Eun Hee; He, Li; Iuvone, P. Michael; Duong, Duc M.; Seyfried, Nicholas T.; Benskey, Matthew J.; Manfredsson, Fredric P.; Jin, Lingjing; Sun, Yi; Wang, Jian Zhi; Ye, Keqiang

doi:10.1038/nsmb.3433

Cited by 157 publications

(175 citation statements)

References 46 publications

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“…It is worth noting that both MAO‐B and α‐Syn protein levels were higher in PD patients than healthy controls. We have recently reported that AEP, an age‐dependent cysteine protease, is highly activated in human PD brains and cleaves α‐Syn at N103, promoting its aggregation and neurotoxicity (Zhang et al , ). Accordingly, α‐Syn N103 was much more abundant in PD brains than controls (Fig E).…”

Section: Resultsmentioning

confidence: 99%

“…Asparagine endopeptidase is an age‐dependent protease that cleaves α‐Syn in PD brains (Zhang et al , ). Wild‐type SNCA transgenic mice display PD‐like pathology and motor deficits between 12 and 18 months of age (Janezic et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…We recently reported that α‐Syn N103 promotes α‐Syn aggregation triggering dopaminergic neurodegeneration, leading to PD pathogenesis (Zhang et al , ). Moreover, inhibition of MAO‐B suppressed α‐Syn‐mediated PD pathology, which was associated with reduced α‐Syn N103 cleavage by AEP.…”

Section: Resultsmentioning

confidence: 99%

“…We recently showed that AEP is highly activated in PD patient brains and cleaves α‐Syn at N103 residue in an age‐dependent manner. Importantly, N103 cleavage greatly escalates α‐Syn aggregation and neurotoxicity (Zhang et al , ). In the current study, we demonstrate that AEP cleavage of α‐Syn N103 is required for MPTP‐induced MAO‐B activation.…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, inhibition of α‐Synuclein (wild‐type and A53T) cleavage by AEP eliminates its pathologic activity. Hence, AEP might play a critical role in mediating the pathogenesis of PD by cleaving α‐Syn (Zhang et al , ). In the current study, we show that α‐Syn selectively binds MAO‐B and elevates its enzymatic activity, and the AEP‐cleaved α‐Syn N103 fragment exhibits the strongest binding affinity and catalytic activity toward MAO‐B.…”

Section: Introductionmentioning

confidence: 99%

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α‐Synuclein stimulation of monoamine oxidase‐B and legumain protease mediates the pathology of Parkinson's disease

et al. 2018

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Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with abnormal dopamine metabolism by MAO-B (monoamine oxidase-B) and intracellular α-Synuclein (α-Syn) aggregates, called the Lewy body. However, the molecular relationship between α-Syn and MAO-B remains unclear. Here, we show that α-Syn directly binds to MAO-B and stimulates its enzymatic activity, which triggers AEP (asparagine endopeptidase; legumain) activation and subsequent α-Syn cleavage at N103, leading to dopaminergic neurodegeneration. Interestingly, the dopamine metabolite, DOPAL, strongly activates AEP, and the N103 fragment of α-Syn binds and activates MAO-B. Accordingly, overexpression of AEP in SNCA transgenic mice elicits α-Syn N103 cleavage and accelerates PD pathogenesis, and inhibition of MAO-B by Rasagiline diminishes α-Syn-mediated PD pathology and motor dysfunction. Moreover, virally mediated expression of α-Syn N103 induces PD pathogenesis in wild-type, but not MAO-B-null mice. Our findings thus support that AEP-mediated cleavage of α-Syn at N103 is required for the association and activation of MAO-B, mediating PD pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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α‐Synuclein stimulation of monoamine oxidase‐B and legumain protease mediates the pathology of Parkinson's disease

et al. 2018

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Carboxy‐terminal truncations of mouse α‐synuclein alter aggregation and prion‐like seeding

et al. 2020

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Edited by Sandro Sonnino a-synuclein (asyn) forms pathologic inclusions in several neurodegenerative diseases termed synucleinopathies. The inclusions are comprised of asyn fibrils harboring prion-like properties. Prion-like activity of asyn has been studied by intracerebral injection of fibrils into mice, where the presence of a species barrier requires the use of mouse asyn. Post-translational modifications to asyn such as carboxy (C)-terminal truncation occur in synucleinopathies, and their implications for prion-like aggregation and seeding are under investigation. Herein, C-truncated forms of asyn found in human disease are recapitulated in mouse asyn to study their seeding activity in vitro, in HEK293T cells, in neuronal-glial culture, and in nontransgenic mice. The results show that C-truncation of mouse asyn accelerates aggregation of asyn but alters prion-like seeding of inclusion formation.

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UNC5C Receptor Proteolytic Cleavage by Active AEP Promotes Dopaminergic Neuronal Degeneration in Parkinson's Disease

et al. 2022

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Netrin‐1 is a chemotropic cue mediating axon growth and neural migration in neuronal development, and its receptors deletion in colorectal cancer and UNC5s act as dependence receptors regulating neuronal apoptosis. Asparagine endopeptidase (AEP) is an age‐dependent protease that cuts human alpha‐synuclein (α‐Syn) at N103 and triggers its aggregation and neurotoxicity. In the current study, it is reported that UNC5C receptor is cleaved by AEP in Parkinson's disease (PD) and facilitates dopaminergic neuronal loss. UNC5C is truncated by active AEP in human α‐SNCA transgenic mice in an age‐dependent manner or induced by neurotoxin rotenone. Moreover, UNC5C is fragmented by AEP in PD brains, inversely correlated with reduced netrin‐1 levels. Netrin‐1 deprivation in primary cultures induces AEP and caspase‐3 activation, triggering UNC5C proteolytic fragmentation and enhancing neuronal loss. Noticeably, blocking UNC5C cleavage by AEP attenuates netrin‐1 deprivation‐elicited neuronal death and motor disorders in netrin flox/flox mice. Overexpression of AEP‐truncated UNC5C intracellular fragment strongly elicits α‐Syn aggregation and dopaminergic loss, locomotor deficits in α‐SNCA transgenic mice. Hence, the findings demonstrate that netrin‐1 reduction and UNC5C truncation by AEP contribute to PD pathogenesis.

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

Cited by 157 publications

References 46 publications

α‐Synuclein stimulation of monoamine oxidase‐B and legumain protease mediates the pathology of Parkinson's disease

α‐Synuclein stimulation of monoamine oxidase‐B and legumain protease mediates the pathology of Parkinson's disease

Carboxy‐terminal truncations of mouse α‐synuclein alter aggregation and prion‐like seeding

UNC5C Receptor Proteolytic Cleavage by Active AEP Promotes Dopaminergic Neuronal Degeneration in Parkinson's Disease

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