Genetic and Pharmacological Approaches to Preventing Neurodegeneration
The Insulin/Insulin-like Growth Factor 1 Signaling (IIS) pathway was first identified as a major modifier of aging in C.elegans. It has since become clear that the ability of this pathway to modify aging is phylogenetically conserved. Aging is a major risk factor for a variety of neurodegenerative diseases including the motor neuron disease, Amyotrophic Lateral Sclerosis (ALS). This raises the possibility that the IIS pathway might have therapeutic potential to modify the disease progression of ALS. In a C. elegans model of ALS we found that decreased IIS had a beneficial effect on ALS pathology in this model. This beneficial effect was dependent on activation of the transcription factor daf-16. To further validate IIS as a potential therapeutic target for treatment of ALS, manipulations of IIS in mammalian cells were investigated for neuroprotective activity. Genetic manipulations that increase the activity of the mammalian ortholog of daf-16, FOXO3, were found to be neuroprotective in a series of in vitro models of ALS toxicity. The small molecule Psammaplysene A (PA) is known to increase the nuclear abundance of FOXO3. PA was also found to be protective in mammalian in vitro models of ALS toxicity as well as a fly and worm model of neurodegeneration. Due to the wide variety of neurodegenerative diseases that share aging as a risk factor, a small molecule modifier of FOXO/daf-16 such as PA could hold great therapeutic potential. Most clinically viable drugs have certain physico-chemical properties that fall within a well-defined set of values, which unfortunately PA does not share. Due to its poor "drug-likness", an investigation into the mechanism of action of PA was undertaken in order to potentially identify more "drug-like" compounds with similar activities. This investigation revealed the heterogeneous nuclear ribonucleoprotein K (HNRNPK) is a direct physical target of PA. PA modifies the ability of HNRNPK to stabilize rRNA but does not affect many of HNRNPK's other functions. How changes in rRNA stability modify IIS or whether these changes definitively underlie PA's neuroprotective mechanism remains to be determined.