mTOR inhibition represses transcription of cholesterol biosynthesis genes and alters cholesterol levels in primary neurons and in the developing brain

Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally downregulated by mTOR complex 1 (mTORC1) inhibition in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. These genes were shared targets of the transcription factors SREBP, SP1 and NF-Y. Reduced expression of these genes directly translated into reduced cholesterol levels pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.