Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases.
View Article and Find Full Text PDFObjectives: The non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insight into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we compared patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both.
Methods: We performed targeted metabolomic analyses of amino acids and broad sphingolipids in sera from a cohort of MacTel (205), HSAN1 (25) and Control (151) participants.
Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves. Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes. Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome, but the mechanistic drivers and downstream consequences of this metabotype remain unclear.
View Article and Find Full Text PDFMacular telangiectasia type 2 (MacTel) is a progressive, late-onset retinal degenerative disease linked to decreased serum levels of serine that elevate circulating levels of a toxic ceramide species, deoxysphingolipids (deoxySLs); however, causal genetic variants that reduce serine levels in patients have not been identified. Here we identify rare, functional variants in the gene encoding the rate-limiting serine biosynthetic enzyme, phosphoglycerate dehydrogenase (PHGDH), as the single locus accounting for a significant fraction of MacTel. Under a dominant collapsing analysis model of a genome-wide enrichment analysis of rare variants predicted to impact protein function in 793 MacTel cases and 17,610 matched controls, the PHGDH gene achieves genome-wide significance (P = 1.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
November 2020
Retinal neovascularization (NV), a leading cause of vision loss, results from localized hypoxia that stabilizes the hypoxia-inducible transcription factors HIF-1α and HIF-2α, enabling the expression of angiogenic factors and genes required to maintain homeostasis under conditions of oxygen stress. HIF transcriptional activity depends on the interaction between its intrinsically disordered C-terminal domain and the transcriptional coactivators CBP/p300. Much effort is currently directed at disrupting protein-protein interactions between disease-associated transcription factors like HIF and their cellular partners.
View Article and Find Full Text PDFMining of integrated public transcriptomic and ChIP-Seq (cistromic) datasets can illuminate functions of mammalian cellular signaling pathways not yet explored in the research literature. Here, we designed a web knowledgebase, the Signaling Pathways Project (SPP), which incorporates community classifications of signaling pathway nodes (receptors, enzymes, transcription factors and co-nodes) and their cognate bioactive small molecules. We then mapped over 10,000 public transcriptomic or cistromic experiments to their pathway node or biosample of study.
View Article and Find Full Text PDFBackground: Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously.
Methods: Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in encoding a subunit of serine palmitoyltransferase (SPT).
Adrenergic stimulation of brown adipose tissue (BAT) induces acute and long-term responses. The acute adrenergic response activates thermogenesis by uncoupling oxidative phosphorylation and enabling increased substrate oxidation. Long-term, adrenergic signaling remodels BAT, inducing adaptive transcriptional changes that expand thermogenic capacity.
View Article and Find Full Text PDFBackground: Peroxisome proliferator activated receptor-alpha (PPARα) is a ubiquitously expressed nuclear receptor. The role of endogenous PPARα in retinal neuronal homeostasis is unknown. Retinal photoreceptors are the highest energy-consuming cells in the body, requiring abundant energy substrates.
View Article and Find Full Text PDFBrown adipose tissue (BAT) thermogenesis relies on a high abundance of mitochondria and the unique expression of the mitochondrial Uncoupling Protein 1 (UCP1), which uncouples substrate oxidation from ATP synthesis. Adrenergic stimulation of brown adipocytes activates UCP1-mediated thermogenesis; it also induces the expression of Ucp1 and other genes important for thermogenesis, thereby endowing adipocytes with higher oxidative and uncoupling capacities. Adipocyte mitochondrial biogenesis and oxidative capacity are controlled by multiple transcription factors, including the estrogen-related receptor (ERR)α.
View Article and Find Full Text PDFPhotoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease.
View Article and Find Full Text PDFTissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine. Current dogma suggests that high-energy-consuming photoreceptors depend on glucose. Here we show that the retina also uses fatty acid β-oxidation for energy.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
August 2014
The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) is widely considered a central transcriptional regulator of adaptive thermogenesis in brown adipose tissue (BAT). However, mice lacking PGC-1α specifically in adipose tissue have only mild thermogenic defects, suggesting the presence of additional regulators. Using the activity of estrogen-related receptors (ERRs), downstream effectors of PGC-1α, as read-out in a high-throughput genome-wide cDNA screen, we identify here growth arrest and DNA-damage-inducible protein 45 γ (GADD45γ) as a cold-induced activator of uncoupling protein 1 (UCP1) and oxidative capacity in BAT.
View Article and Find Full Text PDFEstrogen-related receptors (ERR), ERR alpha (ERRα) and ERR gamma (ERRγ), are orphan nuclear receptors implicated in breast cancer that function similarly in the regulation of oxidative metabolism genes. Paradoxically, in clinical studies, high levels of ERRα are associated with poor outcomes whereas high levels of ERRγ are associated with a favorable course. Recent studies suggest that ERRα may indeed promote breast tumor growth.
View Article and Find Full Text PDF