Antiretroviral treatment reveals a novel role for lysosomes in oligodendrocyte maturation

Abstract

White matter deficits are a common neuropathologic finding in neurologic disorders, including HIV-associated neurocognitive disorders (HAND). In HAND, the persistence of white matter alterations despite suppressive antiretroviral (ARV) therapy suggests that ARVs may be directly contributing to these impairments. Here, we report that a frontline ARV, bictegravir (BIC), significantly attenuates remyelination following cuprizone-mediated demyelination, a model that recapitulates acute demyelination, but has no impact on already formed mature myelin. Mechanistic studies in vitro revealed that treatment with BIC leads to significant decrease in mature oligodendrocytes accompanied by lysosomal de-acidification and impairment of lysosomal degradative capacity with no alterations in lysosomal membrane permeability or total lysosome number. Activation of the endolysosomal cation channel TRPML1 prevents both lysosomal de-acidification and impairment of oligodendrocyte differentiation by BIC. Lastly, we show that de-acidification of lysosomes by compounds that raise lysosomal pH is sufficient to prevent maturation of oligodendrocytes. Overall, this study has uncovered a critical role for lysosomal acidification in modulating oligodendrocyte function and has implications for neurologic diseases characterized by lysosomal dysfunction and white matter abnormalities. Table of ContentsO_ST_ABSMain PointsC_ST_ABSO_LIThe antiretroviral, bictegravir, inhibited remyelination through OPC differentiation blockade and had no effect on mature myelin C_LIO_LIBictegravir inhibits oligodendrocyte differentiation through de-acidification of lysosomes and this was prevented via activation of the lysosomal channel TRPML1 C_LIO_LIDe-acidification of lysosomes by other drugs (e.g. bafilomycin A) is sufficient to inhibit oligodendrocyte maturation C_LI Table of Contents Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/502855v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@12f4d8borg.highwire.dtl.DTLVardef@8be876org.highwire.dtl.DTLVardef@14ad1a0org.highwire.dtl.DTLVardef@108631d_HPS_FORMAT_FIGEXP M_FIG C_FIG