Targeting Cholesterol Homeostasis Improves Recovery in Experimental Optic Neuritis

Area of Science:

• Neuroscience
• Ophthalmology
• Demyelinating Diseases

Background:

• Acute optic neuritis (ON) is a frequent cause of vision loss, often linked to multiple sclerosis (MS).
• Cholesterol recycling is critical for myelin repair following demyelination.
• Gentisic acid (GA) may enhance cholesterol transport.

Purpose of the Study:

• To investigate if gentisic acid (GA) improves retinal ganglion cell (RGC) development and myelination in organoid systems.
• To assess if systemic GA treatment can restore the ocular phenotype in a mouse model of optic neuritis (ON).

Main Methods:

• Treatment of retinal and brain organoids with GA.
• Utilizing a MOG-induced experimental autoimmune encephalomyelitis (EAE) mouse model for ON.
• Evaluating RGC organization, synaptogenesis, and myelination markers (NG2, Olig2).
• Assessing motor function, visual acuity, and optic nerve pathology in EAE mice.

Main Results:

• GA accelerated retinal organoid maturation, improving RGC organization and synaptogenesis.
• GA supplementation increased NG2 and Olig2 expression in brain organoids.
• GA treatment in EAE mice reduced motor impairment, preserved visual function, and lessened demyelination.
• Histopathology showed reduced optic nerve damage and fewer infiltrating cells in GA-treated mice.

Conclusions:

• Augmenting cholesterol transport with GA shows therapeutic potential for optic neuritis.
• GA treatment promotes RGC development, myelination, and functional recovery in demyelinating conditions.
• Targeting cholesterol homeostasis could be a promising strategy for MS rehabilitation.