6533b855fe1ef96bd12b04f0

RESEARCH PRODUCT

Regulation of cholesterol metabolism in the retina under experimental conditions associated with glaucoma

subject

description

Cholesterol is a lipid found in every animal cell and is necessary for its survival. Among its multiple roles in the body, it is a component of cell membranes that is crucial for the maintenance of their structure and fluidity and is thus implicated in the modulation of many signalling pathways. Neurons are especially dependant on cholesterol input since the proper composition of their plasma membrane is required for vesicular exocytosis of neurotransmitters and transduction of the post-synaptic signal. It has been shown that both an excess and a lack of cholesterol is neurotoxic. Moreover, many neurodegenerative diseases, such as Alzheimer’s or Huntington’s disease, have been associated with dysregulation of cholesterol homeostasis, highlighting the need for a fine regulation of its metabolism in nervous tissues. Coordinated actions of neurons and glia, that exhibit complementary functions, are mandatory in that respect. In the brain, astrocytes, the main macroglial cells, may be the major source of cholesterol biosynthesis and export. Neurons, acting as consumers, may be specifically in charge of cholesterol elimination via conversion into 24S-OHC by the CYP46A1 enzyme. This metabolite is likely not only an elimination product of cholesterol but also a signalling molecule in glial cells. It might enable glial cholesterol metabolism to adjust as needed and avoid an overload in brain tissues. In the retina, cholesterol metabolism and its regulation under physiological and pathological conditions remain largely unknown. Müller cells, the major macroglial cells of the retina, could participate in cholesterol synthesis in this tissue even though evidence is still needed. Regarding 24S-OHC, its synthesis is mainly restricted to retinal ganglion cells, neurons responsible for nervous signal transmission from the retina to the brain. Studies performed in our laboratory suggest that CYP46A1 and its product could be implicated in the physiopathology of glaucoma, a disease characterized by ganglion cell degeneration.The present project aims to provide a better understanding of cholesterol metabolism in Müller cells and its potential regulation by 24S-OHC. The goal is also to unveil changes in cholesterol metabolism during the progression of glaucoma by characterizing, at different time points, the molecular players implicated in its biosynthesis, transport and elimination. Our experiments performed on primary Müller cell cultures indicate that these cells possess the molecular machinery to synthesize and export cholesterol and could therefore actively participate in its metabolism in the retina. We also reported a strong hypocholesterolemic effect of 24S-OHC in Müller cells, reinforcing the hypothesis that this compound could be a regulator of cholesterol metabolism in the retina. In an experimental glaucoma model, induced by an elevation in intraocular pressure in rats, we observed major changes in cholesterol metabolism. At the earliest time points, genes implicated in cholesterol biosynthesis and uptake in the retina were upregulated, and cholesterol precursor levels were consecutively and transiently elevated. An important component of our work was to demonstrate that counter-regulatory mechanisms were activated in response to these initial dysregulations, that enabled the maintenance of cholesterol homeostasis in the retina and likely participated in ganglion cell survival.