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

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.

• Authors: Seong Su Kang, Eun Hee Ahn, Zhentao Zhang, Xia Liu, Fredric P Manfredsson, Ivette M Sandoval, Susov Dhakal, P Michael Iuvone, Xuebing Cao, Keqiang Ye
• Journal: The EMBO journal (EMBO J) Vol. 37 Issue 12 (06 15 2018) ISSN: 1460-2075 [Electronic] England
• PMID: 29769405 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors.

Chemical References

• Indans
• Monoamine Oxidase Inhibitors
• Snca protein, mouse
• alpha-Synuclein
• rasagiline
• Monoamine Oxidase
• Cysteine Endopeptidases
• asparaginylendopeptidase
• Dopamine

Topics

• Animals
• Cysteine Endopeptidases (genetics, metabolism)
• Disease Models, Animal
• Dopamine (genetics, metabolism)
• Indans (pharmacology)
• Mice
• Mice, Transgenic
• Monoamine Oxidase (genetics, metabolism)
• Monoamine Oxidase Inhibitors (pharmacology)
• Parkinson Disease (genetics, metabolism, pathology)
• alpha-Synuclein (genetics, metabolism)