SCAP in glia-neuron interactions
In the nervous system, lipids (cholesterol and fatty acids) determine the formation and function of highly specialized membranes, such as myelin and the synaptic membrane. Moreover, lipids serve as precursors for signaling molecules important for brain development and synaptic transmission. The nervous system is shielded from the circulation by the blood-brain and the blood-nerve barriers, and is therefore largely autonomous in lipid synthesis. As such, defects in brain lipid metabolism are associated with neurodevelopmental impairments (e. g., Smith-Lemli-Opitz, Niemann Pick disease type C) and neurodegenerative diseases (e. g., Alzheimer's, Huntington's disease).
Whereas neurons are poor in lipid production, glial cells are active in production and secretion of lipids in vitro. Whether glial cells are lipid suppliers for neuronsin vivo remained to be determined. >
The work presented in this thesis aims to obtain insight into the role of glial lipid metabolism in neuron-glial interactions. It focuses on SCAP (SREBP cleavage-activating protein), a protein responsible for the activation of SREBPs (sterol regulatory element-binding protein) transcription factors, as molecular regulators of lipid synthesis in glial cells.
Combining different technics of molecular biology, genetics and animal behavior we showed that SCAP function in Schwann cells is necessary for timely regulated myelination of peripheral nerves and that deletion of SCAP in astrocytes leads to microcephaly, severe motor dysfunction and premature death. In these two models we have shown that nervous system lipid synthesis relies on SCAP and SREBPs function and that these lipids are essential for nervous system development and function. Importantly, we also showed that these cells partially benefit from external lipid uptake, opening the possibility to use optimized lipid-enriched diets to treat symptoms linked to perturbed lipid metabolism.
The generated mouse models are relevant for human patients with perturbed lipid metabolism, e.g., congenital hypomyelination, Smith-Lemli-Opitz syndrome, Niemann-Pick C and Huntington’s diseases, and multiple sclerosis. The work described in this thesis highlights the importance of these animal models in understanding the consequences of lipid deficiency and in particular, the use of lipid supplementation as a therapeutic strategy.