Regulation of Stress Responses

Neuronal control of cellular stress responses

Protein misfolding is central to the pathology of neurodegenerative diseases. Cells possess natural defense mechanisms to counteract protein misfolding. One such mechanism is the activation of a conserved gene expression program, the so-called heat-shock response, which increases the cellular protein quality control (QC) capacity to help refold and/or degrade misfolded proteins. Experimentally activating this response ameliorates disease pathology, making it a prime target for medical intervention. Yet, in neurodegenerative diseases, cells accumulate misfolded and aggregated proteins but fail to naturally activate this response. Our work over the past years has shown that as in human disease, cells of the metazoan Caenorhabditis elegans do not activate their protein QC machinery upon protein misfolding. This is because in the absence of an external stressor, neuronal activity inhibits the cells’ natural defense against misfolding. However, upon a sensed threat in the environment, the nervous system activates this response even in the absence of protein misfolding through neuromodulators such as serotonin. We have leveraged these findings to train animals using smell to anticipate a proteotoxic assault, and shown that such training can systemically increase protein QC capacity, protecting the animal from actual protein damage. Recent research has shown that the adult brain can be remarkably plastic in response to sensory stimuli. We use C. elegans to understand how specific olfactory training protocols based on neuromodulation can override the neuronal inhibition over the protein QC machinery and activate it upon protein misfolding in neurons, to intervene in neurodegenerative diseases.

Discoveries: 

Do neurons control HSF1 in distant cells?

Thermosensory neurons in C.elegans  control both the immediate expression of HSF1 dependent molecular chaperones upon exposure of animals to stress , as well as the response of cells to the chronic accumulation of misfolded proteins.

PDF iconScience-2008-Prahlad-811-4.pdf PDF iconPNAS-2011-Prahlad-14204-9.pdf

How do neurons cell non-autonomously control HSF1 in C. elegans?

Thermosensory neuronal activity, stimulated using optogenetics, even in the absence of temperature change activates HSF1. This occurs through thermosensory  release of serotonin from serotonergic neurons. Serotonin release triggers the activation of HSF1

PDF iconserotonin paper.pdf  

Why do neurons control such a fundemental cytoprotective response of other cells?

Neurosensory control of stress-induced gene expression allows animals to link prior experience to the regulation of cellular transcriptional responses. 

PDF iconScience signaling paper.pdf