Cellular rejuvenation protects neurons from inflammation-mediated cell death

Area of Science:

• Neuroimmunology
• Neurobiology
• Cellular senescence

Background:

• Multiple sclerosis (MS) involves central nervous system inflammation, leading to demyelination, neuroaxonal injury, and neuronal cell death.
• The precise molecular mechanisms driving neuronal injury and death in MS remain incompletely understood.

Purpose of the Study:

• To investigate the molecular signals and cellular phenotypes associated with neuronal injury in the context of neuroinflammation.
• To explore the potential of cellular rejuvenation as a therapeutic strategy for neuroprotection in neuroimmune disorders.

Main Methods:

• Transcriptome profiling of retinal ganglion cells (RGCs) in experimental autoimmune encephalomyelitis (EAE) mouse models.
• Pathway analysis to identify transcriptional signatures.
• Immunostaining to assess nuclear envelope integrity, chromatin modifications, and DNA damage.
• Adeno-associated virus (AAV)-mediated transduction of RGCs with Oct4-Sox2-Klf4 for transcriptome rejuvenation.

Main Results:

• EAE-induced RGCs exhibited a transcriptional signature resembling aged RGCs with senescent features, a signature also observed in neurons from MS patients.
• Evidence of nuclear envelope alterations, modified chromatin marks, and accumulated DNA damage in affected neurons.
• RGC transduction with Oct4-Sox2-Klf4 enhanced RGC survival in EAE and improved visual acuity.

Conclusions:

• Pathological neuroinflammation in MS induces an aging-like phenotype in neurons.
• Cellular rejuvenation strategies, including gene therapy, show promise for neuroprotection in neuroimmune diseases.
• Senotherapeutic agents may offer a direct therapeutic avenue for conditions like MS.