DNA damage burden causes selective CUX2 neuron loss in neuroinflammation - PubMed
4 hours ago
- #neuroinflammation
- #DNA damage
- #CUX2 neurons
- Neurodegeneration displays regional and cell-type-specific patterns, with upper cortical layer thinning in progressive multiple sclerosis (MS) and selective vulnerability of cortical layer 2/3 excitatory neurons expressing CUX2 (CUX2+ L2/3ENs).
- In MS cortical lesions, CUX2+ L2/3ENs exhibit elevated DNA damage burden, which is replicated in mouse models of demyelination and pan-cortical inflammation, confirming their intrinsic vulnerability.
- CUX2 and activating transcription factor 4 (ATF4) are essential for resilience in L2/3ENs during neuroinflammation by enhancing DNA double-strand break repair, while interferon-γ increases reactive oxygen species, leading to DNA damage-mediated neuronal death and selective depletion of these neurons.