Defining the role of heparan sulfate proteoglycans in APL-1 function in Caenorhabditis elegans
Alzheimer’s Disease (AD) is a neurodegenerative disease that affects more than 7.2 million adults in the U.S. AD is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The b-amyloid peptide is the major component of the plaques and is produced as a cleavage byproduct of the amyloid precursor protein (APP). APP family proteins are present in mammals and the family is considered necessary and essential for viability, although their exact function is still unclear. In Caenorhabditis elegans only one ortholog of APP is present, apl-1. Similar to APP family members, apl-1 is essential for viability; APL-1 is cleaved and releases an extracellular fragment, sAPL-1, into the extracellular matrix (ECM). Based on previous research in the lab, sAPL-1 likely interacts with ECM proteins to guide sAPL-1 to its target receptors. Heparin sulfate proteoglycans (HSPGs), such as LON-2 glypican and UNC-52 perlecan, are likely candidates for the ECM proteins that interact and guide sAPL-1. The disruption of APL-1 causes phenotypical changes, including in learning, reproduction, and memory; these defects are enhanced when HSPG activities are decreased. We also examined how loss of HSPG function affects sAPL-1 clearance. These results suggest that these two proteins play an active role in APL-1 function. Furthermore, we expanded previous research and found that loss of a candidate suppressor gene, GLuCuronosylTransferase-like 6 (glct-6) which encodes for galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase, does not have suppress the apl-1(yn10) lethality. This research helps provide a framework and direction that could help in further understanding both apl-1 function in C. elegans and the relationship of HSPGs and APP clearance in humans.
APP family, APL-1, Alzheimer’s Disease, Heparan Sulfate Proteoglycans (HSPGs), Amyloid Precursor-Like, Developmental Neuroscience, Genetics, Molecular and Cellular Neuroscience, Molecular Genetics
City University of New York - City College
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