Studies on Matrix-Metalloproteinase 13 as a Novel Microglial Inflammatory Agent in Familial Synucleinopathy

Abstract

α-Synuclein is a 140-amino acid protein highly expressed in presynaptic terminals and is also associated with Lewy body pathology found in Lewy Body Dementia (LBD) and Parkinson’s disease (PD) patients. We and others have shown that α-synuclein is a damage associated molecular pattern (DAMP) that directly elicits a proinflammatory response in microglia (i.e., upregulation of tumor necrosis factor-alpha (TNFα), interleukin-1 beta (IL1β), MMP9). α-Synuclein also increases microglial expression of MMP13, an endopeptidase that remodels the extracellular matrix. To better understand the role of MMP13 in synucleinopathies and which cell type is impacted, we used primary mouse cultures. Here we show that cMMP13 did not directly affect hippocampal neuron structure or cytoskeletal proteins. However, exposure of microglia to cMMP13 did lead to morphological changes as well as the release of proinflammatory molecules such as TNFα and MMP-9. Notably, IL1β was not released indicating that the pathway involved in MMP13 activation may be inflammasome independent. Future work will focus on measures of microglial function such as phagocytosis and process motility to better investigate the impact of this MMP on microglia.