Neuroprotection by a Secreted Component of the Cellular Stress Response

Columbia University Health Sciences, New York NY

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Abstract

PROJECT SUMMARY We propose that the secreted luminal domain of the ER membrane-bound transcription factor CREB3L2, TAILS, is a signal for the transmission of adaptive cell stress response in neurons. Previously, we discovered that CNS neurons exposed to variety of degenerative stimuli, including oxidative stress, secrete TAILS. Application of TAILS in a low nanomolar concentration to primary neurons improved survival under oxidative stress. TAILS acts by increasing SHH signaling and increasing the mitochondrial fitness and redox capacity in stressed neurons. In our preliminary experiments, we found that TAILS boosts neuronal resilience not only against oxidative insults but also against stress triggered by the application of the Alzheimer's disease peptide oligomeric Aβ1-42. In this proposal, we are testing our general hypothesis that activation of the integrated stress response in neurons in AD brain triggers the production and secretion of TAILS, which acts as a paracrine signal enhancing SHH signaling thereby boosting resilience to Aβ1-42-induced neuronal stress. The successful completion of this research project will uncover a novel non-cell autonomous branch of adaptive stress signaling that is activated in neurons in response neurodegenerative stress and confers enhanced resilience and mitochondrial function to receiving cells. The expected results from this project will establish TAILS as a stress-regulated modulator of protective neuronal SHH signaling in AD, and it will provide evidence for intercellular communication of the ISR in the mammalian nervous system with implications for neurodegenerative conditions. Moreover, this project will lay the groundwork for two major new directions: (1) the requirement of cell stress for the secretion of TAILS suggests that it might be useful as a biomarker for early degenerative conditions in the brain; and (2) TAILS (or peptides derived from it) are potential compounds for boosting neuronal resilience in the context of AD and other degenerative conditions.