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 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.

GBA1 inactivation in oligodendrocytes affects myelination and induces neurodegenerative hallmarks and lipid dyshomeostasis in mice

“…Moreover, induction of the autophagy/ lysosomal process is known to promote oligodendrocyte maturation [62] and lysosomes are increasingly recognized as central drivers in lipid trafficking and catabolism for the production and recycling of myelin [63,64]. On the other hand, lysosomal alkalinization was recently demonstrated to be sufficient to induce a delay in oligodendrocyte maturation [65], supporting a direct impact of the lysosomal impairment generated by β-glucocerebrosidase dysfunction in this context. Interestingly, disrupted cholesterol trafficking, leading to a punctate distribution as displayed by Oli-neu cells upon β-glucocerebrosidase inactivation, was also found to reduce oligodendrocyte differentiation in an Alzheimer's disease in vitro context, a defect that can be recovered by cyclodextrin that facilitates cholesterol transport to the membrane [66].…”

Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures

“…In addition, mRNA expression of the mature marker proteolipid protein (PLP) was also decreased, suggesting that EVG interfered with the maturation process at the transcriptional level. Alteration of oligodendrocyte differentiation has been reported for several antiretroviral drugs in the protease inhibitor class ( Jensen et al, 2015 ; Festa et al, 2021 ) and the integrase strand transfer inhibitor (INSTI) class ( Roth et al, 2020 ; Festa et al, 2023 ). We previously demonstrated that the INSTI raltegravir (RAL) did not inhibit oligodendrocyte differentiation ( Roth et al, 2020 ), and here, we show that the expression of SREBP-1 and SREBP-2 in oligodendrocytes was not affected by RAL treatment.…”

“…Persistent white matter damage is often observed in persons with HIV on antiretroviral therapy. Although HIV infection itself can cause white matter injury, antiretroviral toxicity may contribute to or prolong myelin damage by altering oligodendrocyte maturation and myelin formation and/or maintenance (Jensen et al, 2015;Roth et al, 2020;Festa et al, 2021Festa et al, , 2023. This, in turn, may help explain at least in part, the high prevalence of HAND among persons with HIV EVG triggers the integrated stress response (ISR) in oligodendrocyte cultures, but the integrated stress response inhibitor (ISRIB) minimally prevents EVG-induced SREBP alterations.…”