The multicellular interplay of microglia in health and disease: lessons from leukodystrophy

Abstract

Microglia are highly dynamic cells crucial for developing and maintaining lifelong brain function and health through their many interactions with essentially all cellular components of the central nervous system. The frequent connection of microglia to leukodystrophies, genetic disorders of the white matter, has highlighted their involvement in the maintenance of white matter integrity. However, the mechanisms that underlie their putative roles in these processes remain largely uncharacterized. Microglia have also been gaining attention as possible therapeutic targets for many neurological conditions, increasing the demand to understand their broad spectrum of functions and the impact of their dysregulation. In this Review, we compare the pathological features of two groups of genetic leukodystrophies: those in which microglial dysfunction holds a central role, termed ‘microgliopathies’, and those in which lysosomal or peroxisomal defects are considered to be the primary driver. The latter are suspected to have notable microglia involvement, as some affected individuals benefit from microglia-replenishing therapy. Based on overlapping pathology, we discuss multiple ways through which aberrant microglia could lead to white matter defects and brain dysfunction. We propose that the study of leukodystrophies, and their extensively multicellular pathology, will benefit from complementing analyses of human patient material with the examination of cellular dynamics in vivo using animal models, such as zebrafish. Together, this will yield important insight into the cell biological mechanisms of microglial impact in the central nervous system, particularly in the development and maintenance of myelin, that will facilitate the development of new, and refinement of existing, therapeutic options for a range of brain diseases.

Dominant-acting CSF1R variants cause microglial depletion and altered astrocytic phenotype in zebrafish and adult-onset leukodystrophy

“…Astrogliosis has been reported in ALSP case studies [ 11 , 58 ], and is considered a general neuropathological hallmark, often characterized by IHC for the highly abundant astrocytic protein GFAP [ 35 ]. Since proteomics revealed a profound upregulation of astrocyte-related proteins, we performed IHC to confirm these findings in situ.…”

“…Zebrafish as a neurobiology model allows exploring cells in embryonic development, in their natural environment by non-invasive in vivo examination. This has led to new fundamental insight in glial biology [ 11 , 71 , 78 ]. In addition, options for genetic targeting have improved, including editing of specific genetic variants identified in human disease as we show here.…”

“…Heterozygous missense variants located in the tyrosine kinase domains (TKDs) of CSF1R have been found to cause the more prevalent adult-onset leukodystrophy, termed ALSP (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) [ 95 ]. Hallmarks of ALSP are motor and cognitive functional decline, often leading to death within several years after disease onset, and neuropathologically progressive white matter lesions, axonal spheroids, pigmented glia and cerebral calcifications [ 1 , 11 , 121 ]. Recent evidence showed that heterozygous CSF1R variants may also be associated with lower density of microglia in ALSP patients [ 83 , 85 , 113 ].…”

Epigenetics and Neuroinflammation Associated With Neurodevelopmental Disorders: A Microglial Perspective

“…The clinical symptoms include cerebral palsy and cognitive decline ( Van der Knaap and Bugiani, 2017 ). Microglial dysfunction plays an important role in the etiology of leukodystrophy ( Garcia et al, 2020 ; Berdowski et al, 2021 ). Homozygous mutations in colony-stimulating factor 1 receptor ( CSF1R ) cause pediatric onset leukoencephalopathy ( Oosterhof et al, 2019 ).…”

The Primary Microglial Leukodystrophies: A Review

“…The present review is focused on a particular group of adult leukodystrophies in which the cause of the disease is linked to mutations in genes expressed in microglial cells. For this reason, these leukodystrophies are considered primary microglial leukodystrophies or primary microglial leukoencephalopathies [ 1 , 7 , 8 , 9 ]. The discovery of new mutations in various genes has allowed the modeling of new concepts of the microglial leukoencephalopathies.…”