A recent study developed by researchers from Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, revealed that in brain cells, changes at the level of lipid metabolism can induce the generation of lipid droplets, which were found to be an indicator of the loss of neurons. The study “Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration” was published in the prestigious journal Cell.
The researchers were able to link lipid droplet accumulation in the glia (non-neuronal cells that provide support and protection for neurons in the brain) to a sign of neurodegeneration. The team used the fruit fly as a tool to uncover the molecular mechanisms behind the loss of neurons. The fruit flies used have mutations in genes, evolutionarily conserved, that correspond to human homologs that lead to neurodegeneration; these are genes responsible for Leigh syndrome, Charcot-Marie-Tooth type 2A2 and ARSAL (autosomal recessive spastic ataxia with leukoencephalopathy). Interestingly, all these mutations disturb the proper functioning of the mitochondria, which is the organelle responsible for generating most of the energy supply of the cells.
Lipid droplets correspond to energy storage depots. They accumulate in the glia in response to defects in neurons’ mitochondria, resulting in high levels of reactive oxygen species (ROS). The accumulation of lipid droplets in glial cells occurs prior to any sign of neurodegeneration. The team, using different fruit fly models and a mouse model, found a new pathway for this accumulation via the incorrect activation of two proteins – c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP).
“This is the first documentation of lipid droplet accumulation in glial cell” said Liu, the first author of the study. The researchers proved that high levels of ROS in the neurons induce the synthesis of lipids and subsequently the formation of lipid droplets in the glial cells. When these lipid droplets suffer oxidative degradation (also called peroxidation) in the presence of ROS, the glia’s ability to support the neurons is compromised.
In fact, the team found that by reducing several components of this pathway, neurodegeneration could be delayed. As an example, treatment with a blood-brain-barrier penetrating antioxidant promoted a delay in the onset of neurodegeneration in both flies and mice.
“There may be a better chance to interfere with disease progression by identifying these diseases at an early stage,” said Bellen. The researchers are now focused on identifying lipid droplets in live animals prior to any sign of neurodegenerative disease.