If someone would ask you whether cancer and neurodegenerative disorders have anything in common, what would you answer? Probably not many things.
However, after meeting with Dr. David Talmage, Professor in the Department of Pharmacological Sciences at Stony Brook University, I was able to learn more about Neuregulin/ErbB signaling pathway, and its significance in both cancer and neuroscience fields. Dr. Talmage has a long record of investigating the underlying mechanisms of ErbB receptor tyrosine kinases in both contexts since he was initially studying their effects in breast cancer, before switching to elucidating their implication in neuropsychiatric disorders. Neuregulins (NRGs) comprise a large family of epidermal growth factor (EGF)-like signaling molecules, which transmit their signals to target cells by interacting with ErbB family receptors. In the early 2000s, Neuregulin-1 (NRG1) protein had already been demonstrated to play a vital role during the development in several organ systems: nervous system, mammary glands, and the heart. However, there was also emerging evidence for involvement of ErbB signals in human disease, and specifically in cancer.
Dr. Talmage, during his first faculty position at the Columbia University Medical Center, focused on this idea, investigating the anticarcinogenic action of retinoids, by exhibiting that these compounds were acting as transcriptional regulators altering the amplitude of signals originating from ErbB receptor tyrosine kinases. In addition, his lab had also demonstrated that in hormone-dependent human breast cancer cells, retinoic acid induces cell growth arrest through protein kinase Calpha (PKCalpha), while PKCbeta (a closely related protein), had opposite effects on cell proliferation and differentiation.
As Dr. Talmage was describing his research pathway and previous accomplishments in the cancer field, it was impossible for me not to ask him the reason or the defining moment that made him change project direction and enter the neuroscience universe. “After NRGs were discovered, they were looking to characterize their different biological functions in the central nervous system (synapse formation, glial formation)”, Dr. Talmage explained. At that point, together with collaborators they were using in vitro synaptic development to check the effects of the different NRG isoforms. “It was amazing to me how these different isoforms with identical ligand-binding domains could elicit very different responses regarding the formation, maintenance, survival and plasticity of synapse connections, upon the same target neurons”, Dr. Talmage said. Remarkably, it was shown that this can be achieved by divergent spatial and timing expression of the isoforms throughout the brain, as well as by differential targeting of NRG ligands to distinct subcellular compartments!
“And that’s when we decided to produce the NRG1-Type III isoform specific knock-out model and to move towards the neuroscience aspect of ErbB signaling pathway”, he said. NRG1-Type III isoform can participate via bidirectional juxtacrine (contact-dependent) signaling and act as an important regulator of cholinergic signaling, regulating both the expression of acetylcholine receptor (AChR) genes and targeting nicotinic AChRs on the neuronal cell surface. After specific manipulation of NRG1 gene, Dr. Talmage and collaborators proposed that changes in NRG1 might contribute to psychiatric disorders by causing imbalance in the fine tuning of connections between neurons in the brain. In 2007, the lab transitioned to Stony Brook University switching entirely over to studies of NRG1-ErbB signaling in the central nervous system.
“Schizophrenia and generally neuropsychiatric disorders are all about balance”, Dr. Talmage noted. “During our NRG1 hypofunction and along with other works showing that aberrant increase of NRG1 function is correlated to similar schizophrenia endophenotypes, it became evident that there is an optimal range of NRG1 concentration in the brain”.
“This gene encodes 20-30 different proteins. So there has to a be differential expression of each isoform and all together to be in balance”. “Hence, we must start specifically targeting isoforms correlated with functions and phenotypes”. And not only this, as Dr. Talmage lab demonstrated recently, the potential impact of parent genotype (i.e. origin of mutation) on the offspring of schizophrenia-relevant behaviors, must be taken in to consideration.
Committed to the goal of studying neurodegenerative disorders and signaling, the Talmage lab’s other main interest has been the investigation of cholinergic circuits as key players for normal executive and mnemonic functioning. Since 1906, when Alois Alzheimer delineated the symptomatology of the disease, a plethora of studies have tested the hypothesis that failures of cholinergic circuitry are responsible for the cognitive impairments observed. “Light-controlled specific cell type activation or inhibition (optogenetics) revolutionized the field and gave us the opportunity to focally target the function of specific cholinergic circuitries. There are different phases of memory function (learning, consolidation, recall, reconsolidation) and the main question for us initially was: Where is acetylcholine contributing? Remarkably, after optogenetically silencing the cholinergic input at basolateral amygdala (fear-related memory area), the animals could not learn and form new memories. While, optogenetic stimulation of specific acetylcholine terminal fields within the basolateral amygdala, could “protect” and slow down the memory extinction.”
“The next most significant steps for us are first to elucidate what is driving subsets of cholinergic neurons to release ACh during these temporal windows of memory phases; and second why there are subsets of cholinergic neurons that are differentially sensitive in Alzheimer’s disease and what is the underlying molecular bases for this resilience”, Dr. Talmage noted.
However, unveiling the cognitive impairment mechanisms is still not enough, since most of the Alzheimer’s disease patients realize the symptomatology 8-10 years after it starts. “Yes, it is true; that is why I believe that PET imaging would be ideal for early identification of cholinergic nuclei integrity loss during the mild disease stages. My dream outcome…would be after studying and identifying the molecular basis of the aforementioned resilience of subsets of cholinergic neurons in AD, to introduce this resilience gene in humans via viral vectors…However, it probably is naive thought, since most probably there is not a single gene of resilience and viral cell targeting is still not cell-specific enough” Dr. Talmage noted.
At the end of our discussion -based on his initial research trajectory at the cancer signaling field- I was still curious to ask Dr. Talmage whether nowadays he considers himself a neurobiologist. Interestingly he replied No… “It would be hubris given the number of people that have devoted their lives to neuroscience; I would consider myself a signaling pathway researcher instead!”
Although risky for most of us, his decision to change fields was probably simple and inevitable in his mind, probably because it was driven by scientific curiosity. I would definitely say that this can give courage to post-docs and young faculty who are willing (but afraid) to change project directions. Let your science instincts and curiosity drive you!
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