Hunter, Skyler, Driscoll, Monica, Toth, Marton, Scerbak, Courtney, Taylor, Barbara, Neri, Christian, Parker, J. Alex, Vayndorf, Elena
[
International Worm Meeting,
2015]
In both C. elegans and humans, the aging nervous system is characterized by decreased synaptic activity, deteriorating short-term and long-term memory, and altered neuronal morphology. Given the overwhelming evidence for proteostasis disruption in neuronal aging, we sought to explain the accumulation of neuronal morphological abnormalities by focusing on protein homeostasis in 6 mechanosensory neurons of aging C. elegans nematodes. We examined the effects of disrupted proteostasis on the integrity of neuronal cytoarchitecture using a transgenic model with an excessively high neuronal protein load, and RNAi knock down of specific genes involved in protein turnover. We found that animals expressing the first 57 amino acids of the human huntingtin gene and an expanded polyglutamine CAG tract (Q128) in mechanosensory neurons accumulate more aberrations that are distinct from those found in animals that express the non-toxic (Q19) number of repeats, or those that express no repeats. We scored and tallied these changes in both the soma and processes and found that they are sometimes associated with improved or reduced function. Next, we used an RNAi candidate gene approach to target genes involved in the maintenance of protein homeostasis in wild-type animals. We found that genes involved in protein turnover play an important role in maintaining the integrity of healthy neurons, and that their knockdown leads to distinct morphological changes in both the process and the soma of wild-type mechanosensory neurons. Taken together, these results suggest that protein homeostasis is critical for maintaining neuronal integrity and function, and that disrupted proteostasis contributes to morphological abnormalities that occur more frequently with advanced age.