Alzheimer's Disease (AD) is a debilitating neurodegenerative condition affecting many elderly individuals. Although AD is generally considered a progressive, age-related condition, a subset of the population is genetically predisposed to developing AD early in life, a condition known as familial Alzheimer's Disease (FAD). FAD is primarily caused by mutations in one of three genes, Amyloid Precursor Protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2), with most mutations occurring in PSEN1. PSEN1 functions the catalytic core of gamma-secretase and is involved in the processing of APP to amyloid beta (Abeta) peptides. and the regulation intracellular Ca2+ signaling. Abeta plaque accumulation has long been regarded as the disease promoting agent controlling AD like neurodegeneration. However, recent studies are showing a lack of correlation between Abeta plaques and AD symptom severity, pointing to the possibility of other mechanisms controlling neurodegeneration. PSEN1 is also known to regulate intracellular Ca2+ signaling, and mutations in PSEN1 have been shown to result in increased reactive oxygen species (ROS) production, oxidative stress, and neurodegeneration as a product of intracellular Ca2+ dysregulation. The mechanisms underlying these intracellular changes however remain unclear. We are looking to investigate the relationship between endoplasmic reticulum (ER)-mitochondrial Ca2+ signaling, mitochondrial ROS production, and neurodegeneration using C. elegans strains harboring mutations in the gene encoding the C. elegans PSEN1 homologue,
sel-12.
sel-12 mutants have been shown to display elevated intracellular Ca2+ levels and increased ER-mitochondrial contacts which are associated with increased mitochondrial Ca2+ uptake, mitochondrial ROS production, and neuronal dysfunction. To understand the mechanism underlying the
sel-12 mitochondrial phenotype, we are investigating the role a specific mitochondrial outer membrane protein, MIRO-1, which has been shown to have roles in mitochondrial trafficking, mitochondrial Ca2+ regulation, and mitochondrial metabolism. By introducing a
miro-1 null mutation into the
sel-12 mutant background, we are investigating whether
miro-1 has a role in the ER- mitochondrial Ca2+ homeostasis and if loss of
miro-1 improves
sel-12 mutant fitness. Thus far, our results indicate that disrupting
miro-1 in the
sel-12 mutant background restores the neurodegenerative phenotype observed in the FAD mutant model system.