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

The EMBO Journal
Seong Su KangKeqiang Ye

Abstract

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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Citations

Dec 4, 2019·The Journal of Clinical Investigation·Seong Su KangKeqiang Ye
Sep 7, 2019·Molecular Neurodegeneration·Anna MasatoLuigi Bubacco
Jan 9, 2019·Frontiers in Cellular Neuroscience·Cong ZhengXuebing Cao
Feb 13, 2020·Pharmacological Reports : PR·Nuno ValeTiago Fleming Outeiro
Jan 9, 2020·Translational Neurodegeneration·Zhentao ZhangKeqiang Ye
Sep 16, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yeqing FangHongcheng Fang
Aug 3, 2021·Frontiers in Pharmacology·Xiaobo WangChun-Feng Liu
Aug 21, 2021·Journal of Nanobiotechnology·Shan-Shan WangMingke Song

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Alpha-Synuclein Aggregation (MDS)

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.