Understanding the folding, sorting, and secretion of neuroprotective growth factors

Proper folding is essential for protein function, while protein misfolding can lead to cellular dysfunction and disease and is thought to contribute to aging. Diseases of protein misfolding, collectively called conformational diseases, include neurodegenerative diseases, certain cancers, type II diabetes, and more. One shared characteristic of conformational diseases is toxic gain-of-function phenotypes caused by misfolded proteins. In neurodegenerative diseases, specifically, misfolded mutant proteins exert toxic gain-of-function phenotypes in only a specific subset of cells despite widespread or, in some cases, ubiquitous expression. In the first part of this dissertation, I investigated the mechanisms that make certain cells susceptible to misfolded proteins. To adequately address this question, I used a novel C. elegans neuroendocrine model with (1) a widely-expressed endogenous protein that has (2) a naturally-occurring mutation which causes misfolding and (3) an associated gain-of-function toxic phenotype in only a subset of cells that express this mutant protein. Using this model, I discovered that a misfolded insulin-like growth factor (IGF/DAF-28) protein exerts a specific "bystander effect" on an unrelated transforming growth factor beta (TGF-[beta]/DAF-7) protein. This bystander effect of misfolded IGF/DAF-28 on an innocent TGF-[beta]/DAF-7 causes cell-specific dysfunction in a sensory neuron, likely through competition for an ER chaperone on which the TGF-[beta]/DAF-7 protein is highly dependent for proper folding. Surprisingly, during this study, I observed opposing polarized localization of DAF-28/IGF and DAF-7/TGF-[beta] proteins within this single sensory neuron. As little is known about polarized sorting of soluble secreted proteins in neurons, in the second part of this dissertation, I investigated the differences in polarized sorting and secretion of DAF-28/IGF, DAF-7/TGF-[beta], and other soluble neuropeptides. My data point to existence of yet-uncharacterized pathways controlling the cellular localization and regulated secretion of these soluble IGF and TGF-[beta] growth factors that may help to better understand how proteins with almost identical functions are differentially regulated in the cell. Based on the neuroprotective roles of local secretion of IGF and TGF-[beta] proteins in the brain, my studies into the understanding mechanisms of DAF-28/IGF and DAF-7/TGF-[beta] biogenesis, sorting, and secretion not only advance the knowledge of basic growth factor biology but can also be used in future development of targeted therapeutic strategies for neurodegenerative diseases.