New functions of the KICSTOR component SZT2

Recent research sheds light on the Mechanistic Target of Rapamycin Complex 1 (mTORC1), a vital regulator of cell growth that responds to various environmental signals. This process is critical in many human diseases, including cancer and epilepsy. At the center of this research is a protein complex called KICSTOR, which acts as a negative regulator of mTORC1 signaling and includes four proteins, one of which is SZT2. This complex is particularly important when our bodies lack essential nutrients such as amino acids or glucose. SZT2, which is primarily found in the brain during development, has been shown to have significant implications for neurological health. Mutations in the SZT2 gene are associated with developmental and epileptic disorders, suggesting that SZT2 plays an important role in the central nervous system. Our current investigation focuses on understanding how these disease-causing mutations affect the functions of SZT2. Specifically, we are investigating whether these mutations affect how SZT2 is produced, how stable it is, and how it interacts with other proteins to form the KICSTOR complex. In particular, we will examine SZT2`s involvement in two critical areas: the regulation of mitochondrial processes - which are essential for energy production in cells - and how it manages oxidative stress, a harmful condition that can damage cells. In addition, we will investigate SZT2`s role in the formation of cilia, tiny hair-like structures that play a crucial role in cell signaling and communication. To conduct our research, we will use a range of advanced scientific techniques, including CRISPR-Cas9 genome editing to modify genes, electron and confocal microscopy for detailed imaging, and mass spectrometry to analyze protein interactions. We will also validate our findings using cortical organoids, which are lab-grown brain-like structures derived from human induced pluripotent stem cells (hiPSCs). This study aims to provide a detailed understanding of how mutations in the SZT2 gene affect its functions, particularly in relation to mTORC1 signaling, mitochondria, and oxidative stress. By uncovering these relationships, we hope to lay the groundwork for future research that could lead to innovative treatments for diseases associated with SZT2 mutations, ultimately improving the quality of life for affected patients. The principal investigators of this project include Lukas A. Huber and Mariana E. Guimarães de Arajo, in collaboration with Ira Ida Skvortsova, Michael W. Hess (Medical University of Innsbruck) as well as Eduard Stephan, and Frank Edenhofer (Leopold Franzens University).

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