Dataset Information

TMX2 is a key regulator of cellular redox state and its dysfunction causes severe brain developmental abnormalities.

ABSTRACT: The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation, dendritic and axonal growth. The relevance of ER-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by biallelic loss of function variants in the Thioredoxin (TRX)-Related Transmembrane-2 (TMX2) gene, detected by exome sequencing in ten affected individuals from seven unrelated families presenting with congenital microcephaly, cortical polymicrogyria and other migration disorders. TMX2 encodes one of the five TMX proteins of the Protein Disulfide Isomerase family and is the first to be linked to human brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER Mitochondria-Associated-Membranes (MAMs), is involved in posttranslational modification and protein folding and undergoes physical interaction with the MAM associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased basal glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox state and identify it as a key adaptive regulator of neuronal proliferation, migration and organization in the developing brain.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neutrophil

DISEASE(S): Brain Cancer

SUBMITTER: Jeroen Demmers

LAB HEAD: Jeroen Demmers

PROVIDER: PXD014064 | Pride | 2019-11-19

REPOSITORIES: Pride

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Publications

TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.

Vandervore Laura V LV Schot Rachel R Milanese Chiara C Smits Daphne J DJ Kasteleijn Esmee E Fry Andrew E AE Pilz Daniela T DT Brock Stefanie S Börklü-Yücel Esra E Post Marco M Bahi-Buisson Nadia N Sánchez-Soler María José MJ van Slegtenhorst Marjon M Keren Boris B Afenjar Alexandra A Coury Stephanie A SA Tan Wen-Hann WH Oegema Renske R de Vries Linda S LS Fawcett Katherine A KA Nikkels Peter G J PGJ Bertoli-Avella Aida A Al Hashem Amal A Alwabel Abdulmalik A AA Tlili-Graiess Kalthoum K Efthymiou Stephanie S Zafar Faisal F Rana Nuzhat N Bibi Farah F Houlden Henry H Maroofian Reza R Person Richard E RE Crunk Amy A Savatt Juliann M JM Turner Lisbeth L Doosti Mohammad M Karimiani Ehsan Ghayoor EG Saadi Nebal Waill NW Akhondian Javad J Lequin Maarten H MH Kayserili Hülya H van der Spek Peter J PJ Jansen Anna C AC Kros Johan M JM Verdijk Robert M RM Milošević Nataša Jovanov NJ Fornerod Maarten M Mastroberardino Pier Giorgio PG Mancini Grazia M S GMS

American journal of human genetics 20191114 6

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated familie ...[more]

PMID: 31735293

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Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, 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’s death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a FUSR521H or a FUSP525L mutation and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette as described previously in our lab. Mutant and control iPSC differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Subsequent lipidomics studies demonstrated defects in myelin lipids, with a reduction of phospholipids in mutant OPCs. Among them, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most two abundant phospholipid in mammalian cells and regulate the mitochondria-associated ER membrane (MAM) integrity. Interestingly, FUSR521H mutant OPCs displayed a decrease in the PC/PE ratio, known to be associated with maintaining membrane (mitochondria) integrity. Proximity ligation assay further indicated that MAM was diminished in mutant OPCs. Moreover, mutant OPCs displayed stronger activation of unfolded protein response markers, a hallmark of increased susceptibility to endoplasmic reticulum (ER) stress, when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca2+ signaling from ER Ca2+ stores. Taken together, these results demonstrate that FUS mutant OPCs display defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and suppressed physiological Ca2+ signaling events.

Dataset Information

TMX2 is a key regulator of cellular redox state and its dysfunction causes severe brain developmental abnormalities.

Publications

TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.

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