ELUCIDATING THE ROLE OF BCAT1 IN MITOCHONDRIAL FUNCTION AND NEURODEVELOPMENT
Branched-chain amino acids (BCAAs) are important nitrogen donors involved in various biochemical processes in the brain and comprise three essential amino acids: Leucine, Isoleucine, and Valine. Regulation of BCAA metabolism influences the central nervous system through multiple mechanisms, including the reversible deamination of BCAAs by branched-chain aminotransferase 1 (BCAT1). While BCAT1 dysregulation is established in cancer metabolism and immune cell function, the role of BCAT1 in neuronal development and mitochondrial function remains elusive. Further, while recent findings link alterations in BCAT1 activity to neurological disorders, few are well-studied in the context of the brain. The work described here combines both in vitro and in vivo modelling with molecular and biochemical techniques to define the function of BCAT1 in the developing brain. First, we show that RNAi-mediated knockdown of BCAT1 significantly impairs hiPSC- and NPC-derived cortical neuron differentiation. Further, we establish a regulatory role for BCAT1 in controlling mitochondrial homeostasis and uncover biallelic variants in BCAT1 as the genetic basis of a previously undefined neurometabolic disorder. Lastly, we show that BCAT1 is critical for post-natal development and cognitive function in mice. Together, these data reveal a novel metabolic mechanism of BCAT1 as a mitochondrial regulator in neurons which in turn alters neuronal development and ultimately animal behavior.
Neuroscience and Neurobiology, Biology, Psychiatry and Psychology
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