Microglia programs under PARK7/DJ-1 deficiency, a genetic cause of Parkinson’s disease, in a DJ-1 mouse model and human induced pluripotent stem cell-derived microglia
It is increasingly evident that dysregulated microglia are implicated in neurodegenerative diseases, such as Parkinson’s disease (PD). The majority of PD cases are idiopathic but in around 10% of patients suffering from PD, the disease is caused by a single mutation with mendelian inheritance. Within our study, we investigate the effects of the loss of the gene PARK7, encoding the protein DJ-1, as its deficiency leads to autosomal recessive early onset PD in humans. DJ-1 is a cytoplasmic protein protecting the cell from reactive oxygen species as well as a myriad of other functions. However, the exact role of DJ-1 in microglia and how its deficiency affects their morphological, transcriptional and functional properties under homeostatic and inflammatory conditions is not fully elucidated yet. To achieve our goals, we took advantage of the DJ-1 KO mouse model and induced pluripotent stem cell-derived microglia knocked out for DJ-1. Furthermore, the study investigates if neuroinflammation induced by lipopolysaccharides injections in DJ-1 KO-mice leads to a change in morphology of microglia. Via confocal imaging of microglia in cortex, hippocampus, striatum and midbrain we applied a computational approach named mic-mac 2.0. This approach can show differences in microglia coverage, polarity and number of edges and nodes per microglia cell in different brain areas. We found no significant differences in edge length and polarity, but there was a trend towards more compactness in DJ-1 KO microglia. Additionally, iPS cell-derived microglia express key homeostatic genes and is a good model for studying DJ-1 function. Taken together, our study aims to elucidate the morphological and functional changes in microglia under DJ-1 deficiency as well as the spatial and temporal points of dysregulation in their immune functions.

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