Disruption of MAM integrity in mutant FUS oligodendroglial progenitors from hiPSCs

• Published in: Acta neuropathologica Vol. 147; no. 1; p. 6
• Main Authors: Zhu, Yingli, Burg, Thibaut, Neyrinck, Katrien, Vervliet, Tim, Nami, Fatemeharefeh, Vervoort, Ellen, Ahuja, Karan, Sassano, Maria Livia, Chai, Yoke Chin, Tharkeshwar, Arun Kumar, De Smedt, Jonathan, Hu, Haibo, Bultynck, Geert, Agostinis, Patrizia, Swinnen, Johannes V., Van Den Bosch, Ludo, da Costa, Rodrigo Furtado Madeiro, Verfaillie, Catherine
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2024; Springer Nature B.V
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - pathology; Calcium (mitochondrial); Calcium signalling; Endoplasmic reticulum; FUS gene; FUS protein; Glial cells; Glial stem cells; Humans; Induced Pluripotent Stem Cells - metabolism; Inhibitory postsynaptic potentials; Lecithin; Lipid metabolism; Medicine; Medicine & Public Health; Metabolism; Mitochondria; Motor neurons; Motor Neurons - metabolism; Mutants; Mutation; Myelin; Neurodegenerative diseases; Neuronal-glial interactions; Neurosciences; Oligodendrocytes; Oligodendroglia - metabolism; Original Paper; Pathology; Phenotypes; Phosphatidylethanolamine; Pluripotency; RNA-Binding Protein FUS - genetics; RNA-Binding Protein FUS - metabolism; Sarcoma; Sox10 protein; Thapsigargin; ER stress; Amyotrophic lateral sclerosis; Mitochondrial dysfunction; MAM disruption; FUS; Lipid defects
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-023-02666-x

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.