Uncovering Neuronal Mechanisms that Control Protein Folding Homeostasis

2013 new Scholar Award in aging

Aging results in a decline in the integrity and function of cells and tissues.  One reason for this decline is thought to be the inevitable accumulation of misfolded and damaged proteins with time accompanied by the collapse in the cells’ protective protein quality control mechanisms to deal with damaged proteins and restore homeostasis.  However, it is unclear why these highly conserved, cytoprotective quality control mechanisms fail to function effectively with age or in age-related diseases.  Using the metazoan, Caenorhabditis elegans we study the specific mechanisms that control the cellular response to the accumulation of protein damage with age. As expected, we found that these mechanisms were not adequately activated upon experimentally induced protein misfolding. Surprisingly, however, this failure was not due to a defect of the protein quality control machinery itself. Instead, it was the result of the nervous system of the organism inhibiting the activation of the very mechanism that was supposed to protect it.   This result, of course, begs the question why such a mechanism exists. How could the inhibition of a seemingly protective mechanism possibly benefit the organism?  Our hypothesis is that the centralized inhibitory control over the cellular protein quality control mechanisms has evolved to prevent their chronic activation which could be detrimental to metazoan growth and reproduction under normal conditions.  In my laboratory we are exploring this question using the model organism C. elegans.  Our goal is to identify conserved signaling mechanisms through which the nervous system may exert its control over the cellular protective machinery.  In addition, we are investigating what the adaptive significance of such neuronal control over protein homeostasis may be for an organism.   The broad conservation of neurohormonal signaling pathways between mammalian systems and C. elegans such as insulin-like signaling, serotonin, etc., validates studying the cell non-autonomous control of protein homeostasis by the nervous system of C. elegans to instruct our understanding of age-related human disease.


Veena Prahlad Ph.D.
Iowa, University of