α-Synuclein stimulation of monoamine oxidase-B and legumain protease mediates the pathology of Parkinson's disease
Document Type
Article
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.
Keywords
delta-secretase (AEP), DOPAL, MPTP, neurodegenerative diseases
Publication Date
6-15-2018
Publication Title
EMBO Journal
ISSN
02614189
E-ISSN
14602075
Volume
37
Issue
12
PubMed ID
29769405
Digital Object Identifier (DOI)
10.15252/embj.201798878
Recommended Citation
Kang, Seong Su; Ahn, Eun Hee; Zhang, Zhentao; Liu, Xia; Manfredsson, Fredric P.; Sandoval, Ivette M.; Dhakal, Susov; Iuvone, P. Michael; Cao, Xuebing; and Ye, Keqiang, "α-Synuclein stimulation of monoamine oxidase-B and legumain protease mediates the pathology of Parkinson's disease" (2018). Translational Neuroscience. 1471.
https://scholar.barrowneuro.org/neurobiology/1471