PhD position: Alterations of cholesterol metabolism in refractory epilepsies

Projet :
Status epilepticus (SE) is a devastating condition consisting in an uninterrupted epileptic seizure lasting over minutes. Despite initial therapeutic control, about 25% SE become refractory. Persisting epileptic seizures increase the risk of excito-toxicity, neuro-inflammation and neuronal death, leading to irreversible neurological sequels, therefore calling for intensive effort to identify novel therapeutic targets to control refractory SE. Among the many physiopathological consequences of SE, a recently discovered pathway involving brain cholesterol homeostasis may offer novel therapeutic opportunities. Whereas cholesterol is present in all membranes, an excess of cholesterol is neurotoxic, through mechanisms that remain largely unknown. Neuronal cholesterol metabolism is controlled in part by the neuron-specific CYP46A1, which catalyzes its degradation into 24-hydroxcholestérol (24-OHc). Recent observations in animal models revealed altered brain cholesterol metabolism with a rapid decline of 24-OHc. In addition, chronic CYP46A1 knockdown results in neuronal cholesterol accumulation, neuronal death and epileptiform activity. This suggests that loss of CYP46A1 upon SE may trigger pathological neuronal cholesterol accumulation leading to excitotoxicity and neuronal death. Thus, preventing brain cholesterol accumulation using for instance statins offers a novel therapeutic perspective that may help reduce the functional consequences of SE.

We propose a transversal and multi-scale approach aiming to explore the functional consequences of a loss of CYP46A1 neuronal expression. Our goal is to better understand how CYP46A1 suppression affects neuronal activity and survival and thereby contribute to anomalous activities following SE.


For more info: projet_ED3C