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

Nat Struct Mol Biol. 2017 Aug;24(8):632-642. doi: 10.1038/nsmb.3433. Epub 2017 Jul 3.

Abstract

Aggregated forms of α-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 α-synuclein are not completely understood. Here we show that asparagine endopeptidase (AEP) cleaves human α-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 α-synuclein at N103 in an age-dependent manner. AEP is highly activated in human brains with PD, and it fragments α-synuclein, which is found aggregated in Lewy bodies. Overexpression of the AEP-cleaved α-synuclein1-103 fragment in the substantia nigra induces both dopaminergic neuronal loss and movement defects in mice. In contrast, inhibition of AEP-mediated cleavage of α-synuclein (wild type and A53T mutant) diminishes α-synuclein's pathologic effects. Together, these findings support AEP's role as a key mediator of α-synuclein-related etiopathological effects in PD.

MeSH terms

  • Animals
  • Asparagine / metabolism*
  • Cysteine Endopeptidases / metabolism*
  • Disease Models, Animal
  • Humans
  • Mice
  • Parkinson Disease / pathology*
  • Protein Aggregation, Pathological
  • Proteins
  • Proteolysis
  • alpha-Synuclein / metabolism*

Substances

  • FAM75A7 protein, human
  • Proteins
  • alpha-Synuclein
  • Asparagine
  • Cysteine Endopeptidases
  • asparaginylendopeptidase