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Updated: Nov 25, 2025
Bioluminescence Imaging of Neuroinflammation in Transgenic Mice After Peripheral Inoculation of Alpha-Synuclein Fibrils
Published on: April 13, 2017
MMP13 Expression Is Increased Following Mutant α-Synuclein Exposure and Promotes Inflammatory Responses in Microglia
Kathryn Sánchez1, Kathleen Maguire-Zeiss1,2
1Department of Biology, Georgetown University, Washington, DC, United States.
Abstract:
α-Synuclein is a 140-amino acid protein that readily misfolds and is associated with the Lewy body pathology found in sporadic and genetic forms of Parkinson's disease. We and others have shown that wild-type α-synuclein is a damage-associated molecular pattern that directly elicits a proinflammatory response in microglia through toll-like receptor activation. Here we investigated the direct effect of oligomeric mutant α-synuclein (A53T) on microglia morphology and activation. We found that misfolded A53T increased quantitative measures of amoeboid cell morphology, NFκB nuclear translocation and the expression of prototypical proinflammatory molecules. We also demonstrated that A53T increased expression of MMP13, a matrix metalloproteinase that remodels the extracellular matrix. To better understand the role of MMP13 in synucleinopathies, we further characterized the role of MMP13 in microglial signaling. We showed exposure of microglia to MMP13 induced a change in morphology and promoted the release of TNFα and MMP9. Notably, IL1β was not released indicating that the pathway involved in MMP13 activation of microglia may be different than the A53T pathway. Lastly, MMP13 increased the expression of CD68 suggesting that the lysosomal pathway might be altered by this MMP. Taken together this study shows that mutant α-synuclein directly induces a proinflammatory phenotype in microglia, which includes the expression of MMP13. In turn, MMP13 directly alters microglia supporting the need for multi-target therapies to treat Parkinson's disease patients.
Insights
Mutant alpha-synuclein (A53T) directly activates microglia, causing inflammation and altering cell structure. This process involves matrix metalloproteinase 13 (MMP13), highlighting potential multi-target therapies for Parkinson's disease.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alpha-synuclein misfolding is central to Parkinson's disease pathology.
- Wild-type alpha-synuclein activates microglia via toll-like receptor pathways.
- The specific effects of mutant alpha-synuclein on microglia require further investigation.
Purpose of the Study:
- To investigate the direct impact of oligomeric mutant alpha-synuclein (A53T) on microglial morphology and activation.
- To elucidate the role of matrix metalloproteinase 13 (MMP13) in mutant alpha-synuclein-induced microglial responses.
- To explore potential therapeutic strategies targeting microglial activation in Parkinson's disease.
Main Methods:
- Treatment of microglia with oligomeric A53T alpha-synuclein.
- Quantitative analysis of microglial morphology (amoeboid shape).
- Assessment of NFκB nuclear translocation and proinflammatory cytokine expression (TNFα, IL1β, MMP9).
- Investigation of MMP13 effects on microglial morphology, cytokine release, and CD68 expression.
Main Results:
- Misfolded A53T significantly increased amoeboid morphology, NFκB translocation, and proinflammatory molecule expression in microglia.
- A53T induced the expression of MMP13, a matrix metalloproteinase.
- MMP13 exposure altered microglial morphology and promoted TNFα and MMP9 release, but not IL1β.
- MMP13 increased CD68 expression, suggesting lysosomal pathway involvement.
Conclusions:
- Mutant alpha-synuclein directly triggers a proinflammatory microglial phenotype, including MMP13 expression.
- MMP13 itself directly modulates microglial function and morphology.
- These findings underscore the need for multi-target therapeutic approaches for Parkinson's disease, addressing both alpha-synuclein and MMP13 pathways.
