The functional role of Transcription Factor E3 (TFE3) on synaptic transmission and synaptic vesicle exocytosis independent of autophagy
Neurodegeneration is commonly seen in the aging population and aging has prone to memory impairment in biological systems in many age-related diseases. Transcription Factor Binding to IGHM Enhancer 3 (TFE3) is a member of the Micropthalmia transcription factor (MiT) family of HLH–leucine zipper transcription factors. Recent studies have demonstrated that TFE3 play a central role in regulating the whole-body energy metabolism and glucose homeostasis. Recently we found a novel function of TFE3 which regulates the synaptic plasticity and synaptic vesicle exocytosis via Complexin 1 (CPLX1) independent of autophagy lysosomal pathway (ALP). The loss of TFE3 in the mice has developed memory abnormalities and synapse dysfunction in the hippocampus when compared to the Wild type mice (WT) during aging. Further we evaluated the learning and memory function by a pair of behavioural studies on the TFE3-KO mice and WT mice. Interestingly we found that the TFE3-KO mice demonstrated a poor learning behaviour and memory deficit compared to the WT mice. In addition, loss of TFE3 reduced the protein expression levels of Synaptophysin, Brain-derived neurotrophic factor, postsynaptic density protein 95 and cAMP response element-binding protein in the hippocampus region when compared to the WT mice. Further to elucidate the synapse function, we did the hippocampal slicing to picturize with transmission electron microscopy demonstrating that loss of TFE3 reduced the synapse formation and vesicle formation compared to the WT mice. Surprisingly, the proteomic profiling of TFE3-KO demonstrated Complexin 1 (CPLX1) was significantly reduced in the TFE3-KO mice brain compared to the WT mice. Further we checked whether TFE3 regulates synaptic functions independent of ALP, we demonstrated the protein levels of autophagic markers in the hippocampus region of TFE3-KO mice. As expected TFE3 did not modulate the ALP markers expression levels, as TFEB compensated the loss of TFE3 in the hippocampus of the brain when compared to the WT mice. Putting together this study will shed a limelight to focus on novel functions of TFE3 on modulation of synaptic transmission and synaptic vesicle exocytosis. This project will play a crucial role in interdisciplinary and collaborative research using Chemical biology, Proteomics and Computational prediction of protein interaction to elucidate the functional role of TFE3. The PhD candidate recruited through this scheme can learn more about molecular biology, in vivo animal study techniques, chemical engineering, and the student will be trained as a strong interdisciplinary researcher with all skill sets.
A post graduate student with molecular biology research background and relevant experimental skills.