Oxidative stress activates the pro-survival TrkA pathway through membrane cholesterol loss.
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.
Iannilli
Francesca
F
Department of Molecular and Developmental Genetics, VIB, Herestraat 49, 3000 Leuven, Belgium.
Sodero
Alejandro O
AO
Ledesma
Maria Dolores
MD
Dotti
Carlos G
CG
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
D007211:Indoles; D017382:Reactive Oxygen Species; D014404:Tubulin; C007293:DAPI; D020122:tert-Butylhydroperoxide; D002784:Cholesterol; D020917:Receptor, trkA