Using C. Elegans to Investigate Neuroprotective and Risk-associated Genes in Alzheimer's Disease

Download or read book Using C. Elegans to Investigate Neuroprotective and Risk-associated Genes in Alzheimer's Disease written by Edward Franklin Griffin and published by . This book was released on 2018 with total page 412 pages. Available in PDF, EPUB and Kindle. Book excerpt: Intracellular accumulation of toxic protein aggregates is the hallmark of neurodegenerative diseases, including Parkinson's (PD), Alzheimer's (AD), and Huntington's. Despite the association of AD with amyloid plaques, composed of the amyloid-Îø (AÎø) peptide, further pursuit into the etiology led to the prevailing model that intracellular accumulation and aggregation is the causative force of AÎø and that the formation of extracellular plaques may be a byproduct of cellular stress response. Thus, understanding the framework of intracellular trafficking and communication in the context of proteotoxicity will provide a clearer understanding of disease progression, in addition to a foundation for identifying therapeutic targets. To do this, we utilized the organism Caenorhabditis elegans to examine the role of vesicular transport between AD and PD models of neurodegeneration. Using these models, we show that the same lysosomal trafficking mechanisms operate in opposing activities between AD and PD models. Previously, we found that overexpression of wild-type and truncated forms of the human vacuolar sorting protein sorting 41 (hVps41) protein reduced neurodegeneration induced by Îł-synuclein, the proteotoxic agent of PD. Here, we show that overexpression of hVps41 or a truncate containing only the CHCR and WD40 domains also reduced AÎø toxicity, but that AÎø-mediated neurodegeneration was affected by intersecting endo-lysosomal pathways. Additionally, the protective effect of hVps41 overexpression was mediated through alternative pathways. Though there is no genetic determinant of AD, variation in the Apolipoprotein E (ApoE) gene is associated with the highest risk of AD. To investigate the relationship between ApoE and AÎø, we generated a transgenic co-expression model that recapitulates the clinical susceptibility profile associated with ApoE. Expression of ApoEÎæ2 reduces neurodegeneration through a protective mechanism shared with ER-derived calcium influx and ApoEÎæ4 mediates mitochondrial interactions that can be exploited through enhancing mitochondrial unfolded protein response to attenuate AÎø. Furthermore, none of the alleles affect lifespan per se, but reduce the depression of lifespan by AÎø. These studies demonstrate the utility of C. elegans as a tool for examining how neurons respond to AD-related stress, with the potential to identify therapeutic targets and provide an animal model of drug discovery.