Antiretroviral treatment reveals a novel role for lysosomes in oligodendrocyte maturation

• Published in: Journal of neurochemistry Vol. 165; no. 5; pp. 722 - 740
• Main Authors: Festa, Lindsay K., Clyde, Abigail E., Long, Caela C., Roth, Lindsay M., Grinspan, Judith B., Jordan‐Sciutto, Kelly L.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2023
• Subjects: Abnormalities; Acidification; Animals; Antiretroviral agents; Cell Differentiation; Cognition; Cuprizone; Deacidification; Demyelinating Diseases - pathology; Demyelination; Disorders; Glial stem cells; HAND; HIV; Human immunodeficiency virus; Impairment; Ion channels; lysosome; Lysosomes; Lysosomes - pathology; Maturation; Membrane permeability; Mice; Mice, Inbred C57BL; Myelin; Myelin Sheath - pathology; Myelination; Neurological diseases; oligodendrocyte; Oligodendrocytes; Oligodendroglia - pathology; Rats; remyelination; Substantia alba; ART; lysosome; HAND; oligodendrocyte; remyelination
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15773

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 utilizing primary rat oligodendrocyte precursor cells (OPCs) revealed that treatment with BIC leads to significant decrease in mature oligodendrocytes accompanied by lysosomal deacidification 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 deacidification and impairment of oligodendrocyte differentiation by BIC. Lastly, we show that deacidification 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. Antiretrovirals (ARVs) used to treat human immunodeficiency virus (HIV) can contribute to white matter abnormalities observed in people living with HIV. In this study, the impact of the frontline ARV, bictegravir (BIC), on oligodendrocyte maturation and remyelination were examined. Following demyelination, administration of BIC significantly inhibited remyelination in the corpus callosum. Furthermore, this inhibition of differentiation by BIC in vitro was driven by lysosomal deacidification and this effect was rescued by the coadministration of the TRPML1 agonist, MLSA1. These findings have identified proper lysosomal acidity as a novel regulator of oligodendrocyte maturation and has implications not only for HIV but other neurologic disorders characterized by white matter impairment.