Recently, a research report published in the journal of Nature Metabolism, scientists from the University of Cincinnati developed a new method to target the molecular processes that activate specific protein complexes. Related research may be expected to help develop new therapies for treating tumor diseases.
Researcher Chenran Wang said that tuberous sclerosis complex (TSC) is a hereditary disorder that promotes the formation of tumors in many different organs, including the brain, affecting up to 50,000 patients’ health each year in the United States. TSC also affects brain function by causing epilepsy and autism in newborns and adults; under this disease, mutations in the Tsc1 and Tsc2 genes result in a loss of tumor suppressor function, leading to over-activation and dysfunction of mTORC1, which in turn produces a variety of TSC symptoms.
As the main regulator of cells, mTORC1 is mainly involved in the activity of most cell growth, but it does not promote autophagy -- a way of self-feeding. In the article, the researchers observed higher autophagy activity in cells without Tsc1, and they developed a double mutant mouse model, which lacks both Tsc1 and autophagy protein FIP200, which is mainly found in the developing nervous system and in the neural stem cells of adults.
Researcher Wang said that, “Utilizing this particular model, we can uncover that autophagy may be a way to maintain high mTORC1 activity and to display abnormal development of neural stem cells lacking Tsc1.” The investigators studied the molecular and metabolic mechanisms of autophagy involved in maintaining high levels of mTORC1 activity and found that it required activation of energy storage in cells (lipids in cells that do not carry Tsc). The breakdown of lipid droplets initiated by the autophagy process can provide fatty acids as an energy source to maintain the energy supply of Tsc1-deficient neural stem cells. Meanwhile, the researchers also used pharmacological methods to target the autophagy process and block fatty acids to treat defects, and to simulate human TSC symptoms in these models.
The results of this study may help researchers understand the pathogenesis of tumor-causing diseases at the molecular level. At the same time, researchers can understand the key signaling pathways and metabolic changes involved in TSC, and mutations in the Tsc gene and over-activation of mTORC1 trigger TSC. Related research results may help researchers develop new therapeutic strategies to treat patients with diseases such as TSC.
Reference:
- Chenran Wang, Michael A. Haas, Fuchun Yang, et al. Autophagic lipid metabolism sustains mTORC1 activity in TSC-deficient neural stem cells, Nature Metabolism (2019). DOI:10.1038/s42255-019-0137-5