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DNA damage burden causes selective CUX2 neuron loss in neuroinflammation

ABSTRACT: Neurodegeneration shows regional and cell-type-specific patterns in ageing and disease1, but the underlying mechanisms for cell type-specific neuronal losses remain poorly understood. Previous studies have shown upper cortical layer thinning in progressive human multiple sclerosis (MS) and that cortical layer 2/3 excitatory neurons (L2/3 ENs) that express CUT like homeobox 2 (CUX2) are selectively vulnerable to degeneration2. Here, we report that L2/3 ENs within MS cortical lesions have elevated DNA damage. DNA damage and selective loss of L2/3 ENs was recapitulated in diverse mouse models of demyelination and pan-cortical inflammation, confirming their intrinsic vulnerability. Functions of Cux2 and Activating transcription factor 4 (Atf4) were essential for resilience of L2/3 ENs during postnatal neuroinflammation, acting in neurons to enhance DNA double strand break repair. Interferon-γ, a cytokine implicated in MS pathogenesis3,4, was sufficient to elevate reactive oxygen species leading to DNA damage-mediated neuronal death in vitro and caused selective depletion of L2/3 neurons in mice. These findings indicate that DNA damage burden and inadequate repair in CUX2+ L2/3 ENs contributes to selective vulnerability in neuroinflammatory injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE314471 | GEO | 2026/02/02

REPOSITORIES: GEO

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Project description:Besides symptoms caused by central nervous system (CNS) lesions, the majority of patients with multiple sclerosis (MS) also exhibit gastrointestinal dysfunction that has frequently been noted, but was not directly linked to the autoimmune etiology of the disease.We studied the enteric nervous system (ENS) in a murine model of MS by histology and electron microscopy. Serum IgG against enteric neurons and enteroglia was measured by ELISA and binding to the ENS was confirmed by immunohistochemistry. Target antigens were identified by mass spectrometry. Gastrointestinal dysfunction was determined by measuring dye transit time. RNA expression profiling was conducted with small intestines of MP4-immunized and control-immunized mice. Data from the mouse model were confirmed in MS patients by immunohistochemistry of the ENS in bowel resectates. In addition, ELISA was performed on plasma samples to detect antibodies against four specific target antigens as identified in the mouse model. ENS degeneration was evident already before the onset of clinical disease in the mouse model. Pathology was predominantly antibody-mediated and caused a significant decrease in gastrointestinal transit, which was associated with severe gliosis of the ENS. Unlike the dense infiltrates that developed in the perivascular compartments of the CNS of MP4-immunized mice, the infiltrates in the ENS consisted of single cells scattered throughout the tissue. RNA expression profiling could support these results, as the expression of inflammatory markers in the small intestine was similar between MP4-immunized and HEL-immunized mice. We identified four specific target antigens derived from enteric neurons and/or enteroglia. Antibodies against all four target antigens were present in MS patients. MS patients also showed gliosis and signs of ENS degeneration in the small intestine. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and the ENS in MS. The presence of ENS pathology prior to CNS degeneration introduces entirely novel ways to explain MS etiology and immunopathogenesis.

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DNA damage burden causes selective CUX2 neuron loss in neuroinflammation

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