Edaravone and mitochondrial transfer as potential therapeutics for vanishing white matter disease astrocyte dysfunction

Abstract

Introduction Previous research has suggested that vanishing white matter disease (VWMD) astrocytes fail to fully differentiate and respond differently to cellular stresses compared to healthy astrocytes. However, few studies have investigated potential VWMD therapeutics in monoculture patient‐derived cell‐based models. Methods To investigate the impact of alterations in astrocyte expression and function in VWMD, astrocytes were differentiated from patient and control induced pluripotent stem cells and analyzed by proteomics, pathway analysis, and functional assays, in the absence and presence of stressors or potential therapeutics. Results Vanishing white matter disease astrocytes demonstrated significantly reduced expression of astrocyte markers and markers of inflammatory activation or cellular stress relative to control astrocytes. These alterations were identified both in the presence and absence of polyinosinic:polycytidylic acid stimuli, which is used to simulate viral infections. Pathway analysis highlighted differential signaling in multiple pathways in VWMD astrocytes, including eukaryotic initiation factor 2 (EIF2) signaling, oxidative stress, oxidative phosphorylation (OXPHOS), mitochondrial function, the unfolded protein response (UPR), phagosome regulation, autophagy, ER stress, tricarboxylic acid cycle (TCA) cycle, glycolysis, tRNA signaling, and senescence pathways. Since oxidative stress and mitochondrial function were two of the key pathways affected, we investigated whether two independent therapeutic strategies could ameliorate astrocyte dysfunction: edaravone treatment and mitochondrial transfer. Edaravone treatment reduced differential VWMD protein expression of the UPR, phagosome regulation, ubiquitination, autophagy, ER stress, senescence, and TCA cycle pathways. Meanwhile, mitochondrial transfer decreased VWMD differential expression of the UPR, glycolysis, calcium transport, phagosome formation, and ER stress pathways, while further modulating EIF2 signaling, tRNA signaling, TCA cycle, and OXPHOS pathways. Mitochondrial transfer also increased the gene and protein expression of the astrocyte marker, glial fibrillary acidic protein (GFAP) in VWMD astrocytes. Conclusion This study provides further insight into the etiology of VWMD astrocytic failure and suggests edaravone and mitochondrial transfer as potential candidate VWMD therapeutics that can ameliorate disease pathways in astrocytes related to oxidative stress, mitochondrial dysfunction, and proteostasis.

Astrocytic glutamate regulation is implicated in the development of stress-related psychiatric disorders

“…There was also an increase in the territory covered by EAAT2+ astrocytes across all profound stress cases in layers IV-V (adulthood: 21%, P adj =2.99×10 -5 , childhood: 21%, P adj =2.43×10 -4 ) as well as an increase in the white matter (15%; P adj =2.31×10 -11 ) of those with childhood stress (Figure 5f). In further support that EAAT2+ astrocytes were distinctly impacted, we performed similar quantification with the total astrocyte marker SOX9 40 and found minimal changes to density with stress stratification in the grey matter (Supplementary Figure 9). This finding corroborates our transcriptomic evidence that there are detectable and persistent differences to astrocytes in human brains that have been exposed to pronounced stress.…”