The astrocyte transcriptome in EAE optic neuritis shows complement activation and reveals a sex difference in...

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Multiple sclerosis (MS) is a neuroinflammatory disease causing optic neuritis and visual disability.
• Current treatments for MS-related optic neuritis do not repair neural damage.
• Identifying cell-specific molecular changes in the optic nerve is crucial for developing new therapies.

Purpose of the Study:

• To characterize the astrocyte-specific transcriptome in the optic nerve during experimental autoimmune encephalomyelitis (EAE), a model for MS.
• To identify potential therapeutic targets for visual disability in MS by examining cell-specific gene expression.

Main Methods:

• Utilized RiboTag technology for astrocyte-specific transcriptome analysis in the EAE model.
• Performed RNA sequencing on optic nerve astrocytes.
• Confirmed protein expression of key molecules using relevant assays.

Main Results:

• Complement Cascade and Cholesterol Biosynthesis pathways were significantly enriched and de-enriched, respectively, in optic nerve astrocytes during EAE.
• Complement component 3 (C3) expression was upregulated at both RNA and protein levels in astrocytes.
• A greater increase in C3-expressing astrocytes and worse retinal ganglion cell (RGC) and axonal loss were observed in female EAE mice compared to males.
• A negative correlation was found between C3-expressing astrocytes and RGC density.

Conclusions:

• Astrocyte-specific gene expression in the optic nerve reveals dysregulation of the complement cascade in MS.
• Increased C3 expression in optic nerve astrocytes is linked to visual damage in experimental MS, with a pronounced effect in females.
• Targeting C3 and related pathways may offer sex-specific therapeutic strategies for optic neuritis in multiple sclerosis.