NOR1 loss relates to inflammation and biological ageing in multiple sclerosis motor cortex

Abstract Cortical neurodegeneration and glial activation are major drivers of disability progression in multiple sclerosis, but the molecular mechanisms underlying these processes remain poorly defined. Members of the NR4A nuclear receptor family are stress-responsive transcription factors that regulate neuronal survival, inflammatory signalling, and cellular adaptation to metabolic and oxidative stress. In particular, neuron-derived orphan receptor 1 (NR4A3) has been implicated in neuroprotective and stress-adaptive responses in other neurological conditions, but its role in multiple sclerosis has not been investigated. Given its dual involvement in neuronal stress regulation and inflammatory modulation, neuron-derived orphan receptor 1 represents a plausible molecular link between chronic neuroinflammation, biological ageing, and cortical neurodegeneration in multiple sclerosis. Here, we examined neuron-derived orphan receptor 1 expression in the motor cortex of post-mortem multiple sclerosis (n = 50) and control (n = 10) cases across lesional and non-lesional cortical layers of the motor cortex. neuron-derived orphan receptor 1 was expressed by various cell types but predominantly localised to the neuronal cytoplasm and was reduced in multiple sclerosis non-lesional grey matter compared to controls, in particular in the functionally relevant layer V. In layer V, neuron-derived orphan receptor 1 loss was linked to exacerbated astrocytic (GFAP+) and microglial/macrophage (CD68+) expression, and higher levels of senescence markers (p19^INK4d, p21^CIP1), suggesting that loss of neuron-derived orphan receptor 1 relates to neuroinflammation and biological ageing processes. In contrast, in layer III, neuron-derived orphan receptor 1 expression was positively associated with neuronal density (NeuN) and Nurr1 expression, a transcription factor from the same NR4A family with established neuroprotective functions. Together, our findings identify neuron-derived orphan receptor 1 as a previously unrecognised, layer-specific regulator of cortical pathology in multiple sclerosis. Loss of neuron-derived orphan receptor 1 in deep-layer projection neurons aligns with inflammatory amplification and ageing-associated stress responses, whereas its preservation in upper layers associates may support neuronal integrity and neuroprotective signalling. These data position neuron-derived orphan receptor 1 as a candidate molecular node linking neuroinflammation, senescence and cortical neurodegeneration in progressive multiple sclerosis, and support that strategies aimed at preserving or restoring neuron-derived orphan receptor 1 activity may support neuron resilience and mitigate cortical disease progression in this cureless disease.