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Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation
Published on: June 26, 2018
Increased alpha-synuclein aggregation following limited cleavage by certain matrix metalloproteinases
Johannes Levin1, Armin Giese, Kai Boetzel
1Neurologische Klinik, Klinikum Grosshadern, Ludwig-Maximilians-Universität München, Germany. jlevin@med.uni-muenchen.de
Experimental Neurology
|November 22, 2008
Summary
Matrix metalloproteinases (MMPs) like MMP-1 and MMP-3 can enhance alpha-synuclein aggregation, a key process in Parkinson's disease (PD). This suggests specific MMP activity may contribute to PD pathogenesis by creating aggregation-promoting protein fragments.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Protein aggregation, particularly alpha-synuclein oligomers, is central to synucleinopathies like Parkinson's disease (PD).
- Matrix metalloproteinases (MMPs) are implicated in PD pathogenesis based on post-mortem and animal studies.
Purpose of the Study:
- To investigate the influence of MMPs and other proteases on alpha-synuclein aggregation using biophysical techniques.
- To characterize the alpha-synuclein fragments generated by proteolysis and identify cleavage sites.
Main Methods:
- Confocal single molecule spectroscopy to monitor alpha-synuclein aggregation.
- Gel electrophoresis (SDS-PAGE) and mass spectrometry (MALDI-ToF) for fragment analysis.
- In vitro digestion of alpha-synuclein with various proteases (MMP-1, MMP-3, MMP-9, Proteinase K, Trypsin).
Main Results:
- Limited digestion by MMP-1 and MMP-3 significantly increased alpha-synuclein aggregation propensity.
- MMP-1, MMP-3, and MMP-9 generated distinct alpha-synuclein fragments, with MMP-3 yielding novel cleavage sites.
- Cleavage between the C-terminal and NAC domains of alpha-synuclein was critical for enhancing aggregation.
Conclusions:
- Specific proteolysis by MMP-1 and MMP-3 promotes alpha-synuclein aggregation in vitro.
- These MMPs may contribute to Parkinson's disease pathogenesis by generating aggregation-enhancing alpha-synuclein fragments.
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