title: Oxidative stress activates the pro-survival TrkA pathway through membrane cholesterol loss.
abstract: Neuronal activity is a highly demanding energetic process, resulting in the gradual accumulation of reactive oxygen species (ROS). Despite comparatively weak anti-oxidant defence systems, neurons outlive the pressure of ROS by activating most robust anti-stress mechanisms. We recently showed that one such mechanism is the activation of the TrkB receptor pathway, in turn determined by the loss of membrane cholesterol. It is not known however what causes the loss of membrane cholesterol. We here show that in differentiated PC12 cells induction of ROS is paralleled by a moderate loss of membrane cholesterol and the activation of the pro-survival TrkA receptor. Pharmacological reduction of cholesterol in non-stressed cells triggers TrkA activation while cholesterol replenishment inhibits receptor activation induced by stress. Moreover, addition of a ROS inhibitor prevented cholesterol loss and receptor activation under stress. These results highlight cholesterol loss as a compensatory protective mechanism against acute stress.
authors.affiliation: Department of Molecular and Developmental Genetics, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Francesca
authors.initials: F
authors.lastname: Iannilli
authors.forename: Alejandro O
authors.initials: AO
authors.lastname: Sodero
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Ledesma
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Dotti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology; D007211:Indoles; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013217:Starvation / Q000503:physiopathology; D013574:Synaptosomes / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D007211:Indoles; D017382:Reactive Oxygen Species; D014404:Tubulin; C007293:DAPI; D020122:tert-Butylhydroperoxide; D002784:Cholesterol; D020917:Receptor, trkA