Vasavda, C. | bioRxiv Science

bioRxiv2020

Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling

Synapses are complex bridges that connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. However, they must remain dynamic in order to adapt to changing inputs. Here, we report that the enzyme biliverdin reductase (BVR) physically links together key molecules in focal adhesion signaling at the synapse. In challenging mice with a battery of neurocognitive tasks, we first discover that BVR null (BVR-/-) mice exhibit profound deficits in learning and memory. We uncover that these deficits may be explained by a loss of focal adhesion signaling that is both transcriptionally and biochemically disrupted in BVR-/- hippocampi. We learn that BVR mediates focal adhesion signaling by physically bridging the initiatory kinases FAK/Pyk2 to the effector kinase Src. Activated Src normally promotes synaptic plasticity by phosphorylating the N-methyl-D-aspartate (NMDA) receptor, but FAK/Pyk2 are unable to bind and stimulate Src without BVR. Src itself is a molecular hub upon which many signaling pathways converge in order to stimulate NMDA neurotransmission, positioning BVR at a prominent intersection of synaptic signaling.

neuroscience↗

bioRxiv2020

Establishing a transcriptome-based drug discovery paradigm for neurodevelopmental disorders

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach called "transcriptome reversal" for these disorders. This approach, originally developed for cancer, attempts to identify compounds that reverse gene-expression signatures associated with disease states.

genomics↗