Background: Multiple sclerosis and cerebral X-linked adrenoleukodystrophy are characterized by acute inflammatory demyelination.
Hypothesis: Pediatric Multiple sclerosis and cerebral X-linked adrenoleukodystrophy share neuroinflammatory response mechanisms for degeneration and repair.
Strategy: Visualisation of acute lesions, repair patterns and identification of regulatory pathways by molecular, histopathological and imaging techniques.
Recent insights from our work indicate that childhood onset multiple sclerosis (MS) and a group of monogenetic neurometabolic myelin disorders share a neuroinflammatory response associated with active demyelination, acute axonal damage and variable oligodendrocyte pathology in the central nervous system (CNS) white matter. Here we strive to understand how the acute inflammatory response acts as a checkpoint to alter myelin/oligodendroglial and axonal pathology and to affect the initiation of repair mechanisms. Our aims are for one, to identify the extent of spontaneous repair in early onset multiple sclerosis and X-linked adrenoleukodystrophy (X-ALD). Furthermore, we want to identify the common or distinct regulatory pathways of inflammation, repair or regeneration failure in human tissue and. Finally we aim to identify and modulate shared pathways in experimental models. Work packages: We will visualize the acute lesion with its degeneration and repair patterns (extent of spontaneous remyelination, detection of mature oligodendrocytes and their precursors, extent of acute axonal damage) in relation to the extent and composition of the inflammatory infiltrate. We will further correlate the findings to already known clinical phenotypes and MRI findings. Furthermore, we will identify the molecular pathways that regulate the acute lesion inflammatory and repair responses in patients on a transcriptome, proteome, and lipidome level. Finally, we will study the effects of a demyelinating and inflammatory insult on immune and repair pathways triggered in a genetic mouse model of X-ALD, with the goal to identify new therapeutic targets that improve axonal and oligodendrocyte survival and enhance myelin repair. This study will explore the inflammatory neurodegeneration and potential repair mechanisms in early onset myelin disorders. The results of this study will not only increase our knowledge about the pathophysiology of acute demyelinating CNS lesions and their repair but will potentially pave the way for novel treatment options including remyelination.
