ABSTRACT
INTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci. METHODS: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aß proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions. RESULTS: We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aß toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex. DISCUSSION: Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/pathology , Genome-Wide Association Study , Polymorphism, Single Nucleotide/genetics , Systems Biology , Temporal Lobe/metabolism , Alzheimer Disease/chemically induced , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Animals, Genetically Modified , Antigens, Neoplasm/genetics , Antigens, Neoplasm/metabolism , Caenorhabditis elegans/genetics , Disease Models, Animal , Early Growth Response Protein 1/genetics , Early Growth Response Protein 1/metabolism , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Heparin-binding EGF-like Growth Factor/genetics , Heparin-binding EGF-like Growth Factor/metabolism , Humans , Male , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Mitochondrial ADP, ATP Translocases/genetics , Mitochondrial ADP, ATP Translocases/metabolism , NADH Dehydrogenase/genetics , NADH Dehydrogenase/metabolism , Protein Interaction Maps , RNA Interference/physiologyABSTRACT
The cyclic adenosine monophosphate-dependent protein kinase A (PKA) pathway helps regulate both cell growth and division, and triglyceride storage and metabolism in response to nutrient status. Studies in yeast show that disruption of this pathway promotes longevity in a manner similar to caloric restriction. Because PKA is highly conserved, it can be studied in mammalian systems. This report describes the metabolic phenotype of mice lacking the PKA catalytic subunit Cbeta. We confirmed that Cbeta has high levels of expression in the brain but also showed moderate levels in liver. Cbeta-null animals had reduced basal PKA activity while appearing overtly normal when fed standard rodent chow. However, the absence of Cbeta protected mice from diet-induced obesity, steatosis, dyslipoproteinemia, and insulin resistance, without any differences in caloric intake or locomotor activity. These findings have relevant pharmacological implications because aging in mammals is characterized by metabolic decline associated with obesity, altered body fat distribution, and insulin resistance.