Citations 2
Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease
Dehghan, Abbas , Pinto, Rui , Karaman, İbrahim , Huang, Jian , Durainayagam, Brenan R., Ghanbari, Mohsen , Nazeer, Areesha , Zhong, Qi , Whiley, Luke , Mustafa, Rima , Solomon, Alina , Ngandu, Tiia , Kanekiyo, Takahisa , Aikawa, Tomonori , Radulescu, Carola I. , Graça, Gonçalo , Camuzeaux, Stéphane , Kaluarachchi, Manuja , Holmes, Elaine , Griffin, Julian L. , Whiley, Luke , Mustafa, Rima , Kanekiyo, Takahisa , Aikawa, Tomonori , Barnes, Samuel J , Chekmeneva, Elena , Kaluarachchi, Manuja R , Holmes, Elaine , Matthews, Paul M , Elliott, Paul , Zhong, Qi , Liggi, Sonia , Kivipelto, Miia , Lewis, Matthew R , Ikram, M. Arfan , Tzoulaki, Ioanna , Matthews, Paul M.
Proceedings of the National Academy of Sciences | October 21, 2022 | Volume: 119 | Issue: 43 | Pages: No page available
Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 ( P = 5.0 × 10 −5 to 1.3 × 10 −44 ). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) ( P = 0.049–1.4 × 10 −5 ), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.
NMRpQuant: an automated software for large scale urinary total protein quantification by one-dimensional 1H NMR profiles
Takis, Panteleimon G. , Vučković, Ivan , Tan, Tricia , Đenić, Aleksandar , Lieske, John C. , Macura, Slobodan , Lewis, Matthew R , Macura, Slobodan I , Lieske, John C , Denic, Aleksandar , Vuckovic, Ivan , Takis, Panteleimon G
Bioinformatics | July 21, 2022 | Volume: 38 | Issue: 18 | Pages: 4437-4439
10.1093/bioinformatics/btac502
AbstractSummary1H nuclear magnetic resonance (NMR) spectroscopy is an established bioanalytical technology for metabolic profiling of biofluids in both clinical and large-scale population screening applications. Recently, urinary protein quantification has been demonstrated using the same 1D 1H NMR experimental data captured for metabolic profiling. Here, we introduce NMRpQuant, a freely available platform that builds on these findings with both novel and further optimized computational NMR approaches for rigorous, automated protein urine quantification. The results are validated by interlaboratory comparisons, demonstrating agreement with clinical/biochemical methodologies, pointing at a ready-to-use tool for routine protein urinalyses.Availability and implementationNMRpQuant was developed on MATLAB programming environment. Source code and Windows/macOS compiled applications are available at https://github.com/pantakis/NMRpQuant, and working examples are available at https://doi.org/10.6084/m9.figshare.18737189.v1.Supplementary informationSupplementary data are available at Bioinformatics online.