Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are CNS inflammatory and neurodegenerative diseases.
• The role of oligodendrocyte death in MS/EAE neurodegeneration is unclear.
• Endoplasmic reticulum (ER) stress response via pancreatic ER kinase (PERK) and activating transcription factor 4 (ATF4) can promote cell survival.

Purpose of the Study:

• To investigate if oligodendrocyte-specific PERK activation reduces neuron loss in EAE.
• To determine the role of ATF4 in oligodendrocytes during EAE pathogenesis.

Main Methods:

• Utilized a mouse model for temporally controlled PERK activation in oligodendrocytes during EAE.
• Generated a separate mouse model for oligodendrocyte-specific ATF4 inactivation in EAE.
• Assessed neuron loss, oligodendrocyte apoptosis, demyelination, axon degeneration, and inflammation.

Main Results:

• Oligodendrocyte-specific PERK activation attenuated neuron loss in the gray matter of EAE mice.
• Inactivation of ATF4 in oligodendrocytes did not affect EAE severity, oligodendrocyte loss, demyelination, axon degeneration, neuron loss, or inflammation.
• PERK activation protected oligodendrocytes without altering inflammation.

Conclusions:

• PERK activation in oligodendrocytes confers neuroprotection in EAE.
• ATF4 in oligodendrocytes is not involved in EAE pathogenesis or the neuroprotective effects of PERK.
• The neuroprotective mechanism of PERK in EAE/MS is independent of ATF4.