DNA damage burden causes selective CUX2 neuron loss in neuroinflammation

Area of Science:

• Neuroscience
• Cell Biology
• Immunology

Background:

• Neurodegeneration exhibits cell-type-specific patterns in aging and disease.
• Upper cortical layer thinning and selective loss of layer 2/3 excitatory neurons (L2/3ENs) expressing CUT-like homeobox 2 (CUX2) are observed in multiple sclerosis (MS).

Purpose of the Study:

• To investigate the mechanisms underlying the selective vulnerability of L2/3ENs in neuroinflammatory conditions like MS.
• To identify the role of CUX2 and activating transcription factor 4 (Atf4) in neuronal resilience.

Main Methods:

• Analysis of L2/3ENs in MS cortical lesions.
• Utilizing mouse models of demyelination and pan-cortical inflammation.
• In vitro studies using Interferon-gamma (IFN-γ) to assess reactive oxygen species (ROS) and DNA damage.

Main Results:

• L2/3ENs in MS lesions show an elevated DNA damage burden.
• Mouse models recapitulated selective L2/3EN loss and DNA damage.
• Cux2 and Atf4 are crucial for L2/3EN resilience by enhancing DNA double-strand break repair.
• IFN-γ induces ROS, leading to DNA damage-mediated neuronal death and selective L2/3 neuron depletion in mice.

Conclusions:

• Elevated DNA damage and impaired repair in CUX2+ L2/3ENs contribute to their selective vulnerability in neuroinflammatory injury.
• This highlights a potential therapeutic target for neurodegenerative diseases like MS.