| Abstrakt: |
Neurodegenerative diseases. such as Alzheimer's Disease and Frontotemporal Dementia. are growing iii prevalence as the population ages. Identifying genes and molecules that can be targeted for new treatments and diagnostics relies on better understanding of the cellular and molecular events that happen throughout the disease process. We have used a Celegans model for Frontorteinporal deinentia to identify a novel role for the RPM-1 signaling pathway in regulating neurodegeneration. RPM-1 is a large, highly conserved ubiquitin ligase that serves as a signaling hub in development of the nervous system. Loss of rpm-1 is protective against degeneration of the worm motor cord in the tauopathy model. This suggests RPM-1 is involved in the neurodegeneration process, acting to promote axon and neuron loss. We assessed known RPM-1 pathway genes for their effects on degeneration of the motor cord. We find that RPM-1 functions upstream of inultiple genes that influence degeneration, including both positive and negative regulation targets. Our candidates include regulators of the endosomal/tysosomal pathway, microtubule stability regulators, and kinases that affect several downstream processes. GLO-4, a guanine nucleotide exchange factor (GEF), works downstream of RPM-1 to promote degeneration. Alternately. the Ser/Thr Kinase and known ubiquitination target. DLK-1, plays a neuroprotective role. Loss of DLK-1 exacerbated degeneration in the tauopathy model. Due to the prominent regulation by DLK-1, we have assessed potential downstream kinases to determine the pathway functioning in degeneration, as well as transcription factors that may be the targets for the kinase pathway. These results show 1) a novel role for RPM-1 signaling. 2) identify the specific kinase cascade involved, and 3) provide insights on potential mechanisms underlying degeneration. [ABSTRACT FROM AUTHOR] |
