Emerging cellular themes in leukodystrophies

Abstract

Leukodystrophies are a broad spectrum of neurological disorders that are characterized primarily by deficiencies in myelin formation. Clinical manifestations of leukodystrophies usually appear during childhood and common symptoms include lack of motor coordination, difficulty with or loss of ambulation, issues with vision and/or hearing, cognitive decline, regression in speech skills, and even seizures. Many cases of leukodystrophy can be attributed to genetic mutations, but they have diverse inheritance patterns (e.g., autosomal recessive, autosomal dominant, or X-linked) and some arise from de novo mutations. In this review, we provide an updated overview of 35 types of leukodystrophies and focus on cellular mechanisms that may underlie these disorders. We find common themes in specialized functions in oligodendrocytes, which are specialized producers of membranes and myelin lipids. These mechanisms include myelin protein defects, lipid processing and peroxisome dysfunction, transcriptional and translational dysregulation, disruptions in cytoskeletal organization, and cell junction defects. In addition, non-cell-autonomous factors in astrocytes and microglia, such as autoimmune reactivity, and intercellular communication, may also play a role in leukodystrophy onset. We hope that highlighting these themes in cellular dysfunction in leukodystrophies may yield conceptual insights on future therapeutic approaches.

Keywords: astrocyte; leukodystrophy; microglia, glia; myelin; oligodendrocyte; white matter (WM).

FIGURE 1

Diverse mechanisms and cell types contribute to hypomyelination in leukodystrophies. In oligodendrocytes, mutations in myelin structural proteins (CNP, PLP1) can lead to thinner myelin sheaths and paranodal loop malformation (CNTNAP1, MAG, MAL). PLP mutations can also lead to aberrant protein aggregation. Other mutations can affect the function of organelles that participate in lipid metabolism and catabolism, such as peroxisomes (ABCD1, HSD17B4, PEX family genes) and lysosomes (ARSA, FUCA1, GALC, GLA, GLB1, PSAP). These defects can also lead to toxic lipid accumulation that builds up in the bloodstream (GLA) or activate astrocytes and microglia (ARSA). Finally, mutations affecting transcription factors (NKX6-2, SOX10), transcriptional machinery (POLR3 genes) and translation machinery (DARS1, eIF2B genes, EPRS1, RARS1) cause impair differentiation of oligodendrocytes and reduce production of myelin proteins. Defects in microtubules that project toward and within the myelin sheath (TUBB4A) as well as in PI4K signaling pathways that contribute to wrapping (FAM126A) can affect myelin sheath growth. Mutations in mitochondrial genes can lead to lipid processing defects (CYP27A1), aberrant activation of apoptotic pathways (AIFM1), and metabolic issues (D2HGDH, IHD2, L2HGDH, SLC25A1). Other pathways, such as nuclear envelope integrity (LB1) and zinc efflux (TMEM163) can also affect oligodendrocyte health. In astrocytes, intermediate filament protein mutations (GFAP) can lead to its aggregation and formation of Rosenthal fibers. Mutations affecting gap junctions can disrupt cell junctions between astrocytes and oligodendrocytes (GJA1, GJC2) and between astrocytes and vasculature (HEPACAM/GLIALCAM, MLC1). Mutations affecting nucleic-acid sensors (ADAR1, IFIH1, RNASEH2 genes, SAMHD1, TREX1) can activate an immune response and release of interferons from astrocytes. In microglia, mutations in cytokine receptors (CSF1R) can affect microglial proliferation, differentiation, and activation. Finally, mutations affecting lipid processing (ARSA, D2HGDH, IHD2, L2HGDH, SLC25A1) can lead to aberrant lipid accumulation, which can activate microglia and astrocytes.