Disruption of MAM integrity in mutant FUS oligodendroglial progenitors from hiPSCs.

Autor: Zhu Y; Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000, Leuven, Belgium. yingli.zhu@kuleuven.be., Burg T; Department of Neurosciences, Experimental Neurology, KU Leuven, Leuven Brain Institute (LBI), 3000, Leuven, Belgium.; Laboratory of Neurobiology, VIB, Center for Brain and Disease Research, 3000, Leuven, Belgium., Neyrinck K; Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000, Leuven, Belgium., Vervliet T; Laboratory of Molecular and Cellular Signalling, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium., Nami F; Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000, Leuven, Belgium., Vervoort E; Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.; Center for Cancer Biology, VIB, 3000, Leuven, Belgium., Ahuja K; Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000, Leuven, Belgium.; Animal Physiology and Neurobiology Section, Department of Biology, Neural Circuit Development and Regeneration Research Group, 3000, Leuven, Belgium., Sassano ML; Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.; Center for Cancer Biology, VIB, 3000, Leuven, Belgium., Chai YC; Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000, Leuven, Belgium., Tharkeshwar AK; Department of Neurosciences, Experimental Neurology, KU Leuven, Leuven Brain Institute (LBI), 3000, Leuven, Belgium.; Laboratory of Neurobiology, VIB, Center for Brain and Disease Research, 3000, Leuven, Belgium., De Smedt J; Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000, Leuven, Belgium., Hu H; National Engineering Research Center for Modernization of Traditional Chinese Medicine-Hakka Medical Resources Branch, School of Pharmacy, Gannan Medical University, Ganzhou, China., Bultynck G; Laboratory of Molecular and Cellular Signalling, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium., Agostinis P; Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.; Center for Cancer Biology, VIB, 3000, Leuven, Belgium., Swinnen JV; Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, 3000, Leuven, Belgium., Van Den Bosch L; Department of Neurosciences, Experimental Neurology, KU Leuven, Leuven Brain Institute (LBI), 3000, Leuven, Belgium.; Laboratory of Neurobiology, VIB, Center for Brain and Disease Research, 3000, Leuven, Belgium., da Costa RFM; Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000, Leuven, Belgium., Verfaillie C; Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000, Leuven, Belgium.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2024 Jan 03; Vol. 147 (1), pp. 6. Date of Electronic Publication: 2024 Jan 03.
DOI: 10.1007/s00401-023-02666-x
Abstrakt: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late-onset ALS. Although ALS results from MN death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a R521H or a P525L mutation in FUS and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette. Mutant and control iPSCs differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Lipidomic studies demonstrated defects in myelin-related lipids, with a reduction of glycerophospholipids in mutant OPCs. Interestingly, FUS R521H OPCs displayed a decrease in the phosphatidylcholine/phosphatidylethanolamine ratio, known to be associated with maintaining membrane integrity. A proximity ligation assay further indicated that mitochondria-associated endoplasmic reticulum membranes (MAM) were diminished in both mutant FUS OPCs. Moreover, both mutant FUS OPCs displayed increased susceptibility to ER stress when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca 2+ signaling from ER Ca 2+ stores. Taken together, these results demonstrate a pathological role of mutant FUS in OPCs, causing defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and with suppressed physiological Ca 2+ signaling. As such, further exploration of the role of oligodendrocyte dysfunction in the demise of MNs is crucial and will provide new insights into the complex cellular mechanisms underlying ALS.
(© 2024. The Author(s).)
Databáze: MEDLINE
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