Spatial and functional characterization of neuronal lipids in health and disease
Biochemistry
Cell Biology
Final Report Abstract
Understanding the brain and its diseases will require a deep understanding of the biology of its cells. While much has been learned about neuronal RNAs and proteins, little is known about the composition and functions of lipids in neurons. Lipids play central roles in the biology of neurons and have been implicated in a wide range of diseases. Thus, we differentiated human induced pluripotent stem cells ( iPSCs ) into neurons and by mass-spectrometry based lipidomics we noted a significant increase of plasmalogen lipid species in the mature compared to the immature and early differentiated neurons. Recently, the gene, PEDS1, has been shown to encode a desaturase that introduces the characteristic vinyl ether double bond into plasmalogens. In line with the plasmalogen increase in mature neurons, PEDS1 RNA levels were also increased. Therefore, to investigate the plasmalogen functions in these cells, we used CRISPR cas9 technology to knock out PEDS1 gene. Of note, neurons lacking plasmalogens exhibit alteration of mitochondrial morphology and respiration with increase of ROS production. Plasmalogen lipids are believed to shield cells from the damaging effects of reactive oxygen species. To investigate this, we cultured neurons in a medium lacking antioxidants deliberately exposing them to chronic, low-level of oxidative stress. Surprisingly, the absence of PEDS1, a key enzyme involved in plasmalogen biosynthesis, led to a drastic neuronal cell death under these conditions. Subsequent investigations unveiled that neurons deficient in plasmalogen lipids exhibited vulnerability to a specific type of cell death known as ferroptosis. Our ongoing and future studies aim to understand deeper the intricate molecular mechanisms through which plasmalogen lipids influence oxidative homeostasis and potentially trigger ferroptosis in neuronal cells. Understanding these mechanisms is fundamental for expanding our comprehension of neuronal biology. Moreover, this research holds immense promise in uncovering novel therapeutic avenues to combat brain diseases, particularly neurodegenerative disorders.
