Synaptic Metal Ion Dynamics and Signaling
The mobility and stability of proteins and ligands in space determine the initiation of cellular signaling. Transition metal ions such as zinc and copper act as ligands and regulate many fundamental biological processes by binding to proteins and modifying their function. Indeed, more than 20% of the human genome encodes for metal binding proteins, which includes signaling proteins, enzymes, and a large fraction of factors that regulate gene expression, potentially rendering metals as a master regulator of cellular processes. To understand the function of metal ions as a signaling entity, it is crucial to understand the spatial dynamics of labile metal ions and their regulation in the cellular microenvironment. Albeit severe technological challenges to study metals ions, latest advances in the field of metallochemistry resulted in the development of an array of new tools such as sensors or probes, including genetically encoded fluorescent indicators, to monitor metal ion dynamics with high sensitivity and specificity, opening up possibilities to investigate the vast potential of metal ion signaling in cellular function and dysfunction.
Why is metal ion signalling important in the study of the brain?
Metal ion dyshomeostasis is prevalently exhibited in both neurodegenerative and psychiatric diseases in humans suggesting a crucial role for metal ions in normal function of neuronal cell biological processes. Furthermore, several key synaptic proteins (e.g. NR1, Shank3) whose mutations are implicated in prominent neurological disorders are metal binding proteins suggesting that disruption of the local metal environment may be involved in the aetiology of many neurological conditions. Interestingly, latest synaptic proteomics data reveal the presence of abundant synaptic metal binding proteins suggesting a significant role of metal ion signaling in synapse function and dysfunction. However, the role of metals ions in synapse physiology and pathology is poorly understood and warrants renewed efforts with an interdisciplinary approach to delineate the chemistry in synaptic biology.
We work on the hypothesis that transition metal ions act as mobile signals and can serve as dynamic regulators of synapse function and local cell biological mechanisms owing to the presence of abundant protein sensors, with binding affinities comparable to the physiological local metal ion concentration.
The broad research interest is to investigate the role of metal ions in information processing in neurons. Do neuronal synaptic and action potentials affect cellular metal homeostasis and how do the local metal ion dynamics contribute to cellular and synaptic signaling? What are the synaptic proteins that are functionally regulated by local metal ion dynamics and how does it affect synaptic molecular logic and local computing? These broad questions are addressed in individual projects focusing on specific metal ions and proteins.
Our recent work revealed the generation of miRNA and inhibition of local protein synthesis in single spines following synaptic activation suggesting complete outsourcing of complex cell biological mechanisms to distant synapses from the neuronal cell body. We are particularly interested in how these local cell biological mechanisms are affected by metal ion dynamics and how this is regulated by synaptic activity and plasticity. To address various questions, we use advanced live-cell imaging, electrophysiology, and biochemical approaches in brain tissues and neuronal cultures.