Fig. 3.

Loss of microglial functions could lead to white matter degeneration by affecting multiple intercellular connections. Routes whereby microglia, directly or indirectly, affect the white matter (WM) have been supported by data from experimental studies as described here; however, their relevance to disease remains to be fully explored. Astrocytes compensate for a lack of microglial phagocytosis by becoming more phagocytic, although they are less efficient than microglia and this response may result in the neglect of critical astrocytic functions. Together with the increased astrocytic reactivity observed in leukodystrophies, this can result in disturbed lipid and metabolic supply to oligodendrocytes (OL) and an unsupportive ECM environment for OPCs. Additionally, altered interactions between the BBB and astrocytic end-feet can perturb metabolic supply to brain cells. Aberrant microglia can lead to insufficient trophic support for OPCs and oligodendrocytes, and a diminished oligodendrocyte lineage. Aberrant microglia may also exhibit perturbed clearance and pruning capacity and contribute to impaired remyelination. Both aberrant microglia and affected astrocytes can cause neuronal stress due to neurotoxicity, ineffective phagocytosis and/or dysregulation of neuroactivity. Axonal pathology and abnormal neuronal activation can affect myelination and, in turn, the degeneration of myelin results in a loss of metabolic support for axons. In sum, white matter degeneration in leukodystrophies is likely preceded by distinct effects of aberrant microglia, possibly forming a ‘perfect storm’ of parallel effects particularly detrimental for the myelinated white matter tracts. Solid arrows indicate established interaction/consequence. Dashed arrows indicate hypothesized interaction/consequence in leukodystrophic brain.