title: Defective HIF signaling pathway and brain response to hypoxia in neurodegenerative diseases: not an "iffy" question!
abstract: Brain structural and functional integrity exquisitely relies on a regular supply of oxygen. In order to circumvent the potential deleterious consequences of deficient oxygen availability, brain triggers endogenous adaptive and pro-survival mechanisms - a phenomenon known as brain hypoxic tolerance. The highly conserved hypoxia-inducible family (HIF) of transcription factors is the "headquarter" of the homeostatic response of the brain to hypoxia. HIF acts as a cellular oxygen sensor and regulates the expression of proteins involved in a broad range of biological processes, including neurogenesis, angiogenesis, erythropoiesis, and glucose metabolism, and thus, enables brain cells to survive in low-oxygen conditions. Hypoxia, as well as hypoxia-reoxygenation, is intimately implicated in the clinical and pathological course of several neurodegenerative diseases. Thus, two major questions can arise: Is HIF signaling and brain response to hypoxia compromised in neurodegenerative diseases? If so, are HIF stabilizers a possible therapeutic strategy to halt or prevent the progression of neurodegenerative diseases? This review highlights the current knowledge pertaining the role of HIF on brain response to hypoxia and its close association with the development of Alzheimer's, and Parkinson's disease and amyotrophic lateral sclerosis. Finally, the potential therapeutic effects of HIF stabilizers (deferoxamine, clioquinol, M30, HLA20, DHB, FG0041, and VK-28) against the symptomatic and neuropathological features of the abovementioned neurodegenerative diseases will be discussed.
authors.affiliation: CNC- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. sonia.correia@cnc.uc.pt.
authors.forename: Sónia C
authors.initials: SC
authors.lastname: Correia
authors.forename: Cristina
authors.initials: C
authors.lastname: Carvalho
authors.forename: Susana
authors.initials: S
authors.lastname: Cardoso
authors.forename: Renato X
authors.initials: RX
authors.lastname: Santos
authors.forename: Ana I
authors.initials: AI
authors.lastname: Plácido
authors.forename: Emanuel
authors.initials: E
authors.lastname: Candeias
authors.forename: Ana I
authors.initials: AI
authors.lastname: Duarte
authors.forename: Paula I
authors.initials: PI
authors.lastname: Moreira
mesh_terms: D000818:Animals; D001343:Autophagy; D001921:Brain / Q000503:physiopathology*; D004920:Erythropoiesis; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D018919:Neovascularization, Physiologic; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000503:physiopathology; D055495:Neurogenesis; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A