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OXIDATIVE STRESS IN THE PATHOGENESIS OF MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS (MLC): TOWARD THE IDENTIFICATION OF POSSIBLE THERAPEUTIC TARGETS
Sara Spositoand 11 co-authors
Istituto Superiore di Sanità
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS06-09PM-054
Presentation
Date TBA
Board: PS06-09PM-054
Event Information
Poster Board
PS06-09PM-054
Poster
View posterAbstract
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic leukodystrophy caused by mutations in the astrocytic membrane protein MLC1. Patients present with macrocephaly, brain edema, cysts, and white matter vacuolation, leading to motor dysfunction, epilepsy, and cognitive delay. Our previous studies in cellular models showed that MLC1 protects astrocytes from osmotic and inflammatory stress. However, MLC1 function and the molecular mechanisms underlying brain pathology remain unclear, limiting therapeutic development. Based on the observation of MLC1 activation in response to oxidant treatment (hydrogen peroxide) in primary rat astrocytes and U251 astrocytoma cells overexpressing wild-type (WT), but not mutant MLC1, we hypothesized an involvement of MLC1 in the astrocytic response to oxidant insults. By characterizing U251 cells, we found that expression of WT MLC1 downregulated Nrf2, the master transcriptional regulator of the cellular antioxidant response, and downstream signaling pathways constitutively activated in these tumoral cells, suggesting a protective role for MLC1 against oxidative insult. In addition, MLC1 mutant–expressing cells showed higher levels of lipid peroxidation and lower mitochondrial membrane potential compared to MLC1 WT–expressing cells, supporting a protective role for MLC1 against oxidative stress. To confirm these findings in a patient-relevant model, we analyzed human astrocytes differentiated from iPSCs of MLC patients and healthy donors. Proteomic, biochemical, and imaging analyses revealed increased oxidative stress and mitochondrial dysfunction in patient cells. Overall, these results indicated that oxidative stress can be part of MLC pathogenesis, supporting the potential of antioxidant-based strategies to slow or halt MLC progression.
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