Cellular rejuvenation protects neurons from inflammation mediated cell death

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Multiple sclerosis (MS) involves central nervous system inflammation, leading to demyelination and neuronal damage.
• Retinal ganglion cells (RGCs) in MS patients and models undergo axonal injury and death.
• The molecular mechanisms driving neuronal damage in MS are not fully understood.

Approach:

• RGCs were isolated from mice with experimental autoimmune encephalomyelitis (EAE), a model for MS.
• RNA-sequencing and ATAC-sequencing were performed on RGCs to analyze molecular changes.
• Single-nucleus RNA-sequencing was used to analyze neurons from human MS patients.

Key Points:

• RGCs in EAE mice and human MS patients displayed a senescence-like molecular signature, similar to aged neurons.
• Neuronal changes included nuclear envelope alterations, modified chromatin marks, and DNA damage.
• Overexpressing Oct4, Sox2, and Klf4 in RGCs promoted a more youthful epigenetic state and enhanced RGC survival.

Conclusions:

• This study identifies a novel senescent-like phenotype in neurons affected by MS.
• Rejuvenating the aged transcriptome of RGCs improved neuronal survival and visual acuity in the EAE model.
• Age rejuvenation and senotherapeutic approaches may offer neuroprotection in autoimmune disorders like MS.