Background: Neuromyelitis optica (NMO) causes CNS lesions with primary astrocytic pathology. Little is known about how damage spreads and is contained in such lesions, or what recovery mechanisms they use.
Hypothesis: Checkpoints for short and long-term axonal recovery in NMO involve the axon cytoskeleton, and lesion repopulation with “protective” vs. “inflammatory” astrocytes, respectively.
Strategy: To use imaging and omics- profiling to explore axon recovery in NMO-related white and grey matter lesions induced by NMO patient IgG, which we will compare to human pathology.
In this project, we aim to understand – in parallel work on animal models and patient-derived tissues – how central nervous system (CNS) lesions of “astrocytopathic” origin recover. Such lesions are characteristic of neuromyelitis optica (NMO), an antibody-mediated CNS autoimmune disease. A conundrum in NMO research is why lesions that primarily target astrocytes, a rather plastic and resilient cell type, are characterized by comparably limited clinical recovery. The axonal injury that is found in NMO is poorly characterized and its relationship to other forms of inflammatory axon injury, as e.g. in multiple sclerosis (MS), is not known. We have obtained preliminary data showing that acute ablation of astrocytes by NMO antisera can cause a unique form of potentially reversible axon injury. Moreover, others and we have also shown that an early sign of lesion repair in NMO and its animal models is repopulation with immature, spindle-shaped astrocytes within days. Based on recent results on axon loss in several spinal pathologies and on “Janus-faced” roles of astrocytes in a range of CNS disorders, including MS, we will explore the checkpoints of acute and chronic neuronal recovery in NMO-related lesions. We hypothesize that the short-term fate of axons is determined by axon-intrinsic checkpoints, such as cytoskeletal disruption, while long-term lesion fate is decided by extrinsic signalling checkpoints that control regenerative vs. gliotic astrocyte repopulation. This either re-establishes the original tissue homeostasis allowing for recovery, or creates a lasting dystrophic micromilieu and neurodegeneration. Moreover, the pathology of NMO is not restricted to white matter tracts, but also affects cortical grey matter. Interestingly, such cortical lesions differ in their composite of glial injury from white matter lesions. For instance, in cortical NMO lesions myelin is preserved, while white matter lesions are demyelinated. Thus, local differences in tissue micromilieu also likely represent determinant of subsequent recovery. In this project, we thus plan to explore the differential contribution of intrinsic and extrinsic checkpoints in axon recovery in NMO-related white and grey matter lesions. By using modelling of NMO-related spinal and cortical pathology in mice, in vivo imaging, ultrastructural and molecular profiling, as well as comparison to human NMO pathology, we will address the following specific aims:
Aim ❶ Profile acute and chronic NMO-related lesions for potential recovery checkpoints
Aim ❷ Elucidate intrinsic checkpoints of acute axon degeneration or recovery
Aim ❸ Explore the extrinsic checkpoints of chronic lesion recovery vs. scarring