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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133483 | GEO | 2019/12/31

REPOSITORIES: GEO

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Project description:SEPN1 is a type II protein of the endoplasmic reticulum (ER) whose loss of function gives rise to a collection of debilitating autosomal recessive myopathies gathered under the umbrella term of SEPN1-related myopathy (RM). At the moment, SEPN1-RM lacks an effective pharmacological treatment; thus, the medical management of the disease is only supportive. The potentially fatal diaphragmatic weakness leading to respiratory insufficiency in patients still ambulant is the main reason for medical concerns. Thus, studies on SEPN1-RM pathogenesis are necessary to implement a targeted pharmacological therapy aimed at relieving the general muscle weakness and the more worrisome diaphragmatic dysfunction. Here, we show a physical and functional interaction between SEPN1 and the ER stress mediator ERO1 alpha (henceforth, ERO1). Both SEPN1 and ERO1 are involved in the redox regulation of proteins into the ER, although in an opposite way SEPN1 imposes a less oxidant ER poise while ERO1 a more oxidant one, conceivable with a reductase function of SEPN1 and an oxidase one of ERO1. Furthermore, both are mainly localized in a region of the ER in close contact with mitochondria termed mitochondria-associated membranes (MAMs) and their loss impacts oppositely on the short-range MAMs, thereby impinging ER-mitochondria Ca2+ dynamics, OXPHOS, and bioenergetics. We find that ERO1 depletion restores the impaired short-range MAMs due to SEPN1 loss together with mitochondrial ATP. ERO1 knockout in a mouse background of SEPN1 loss blunts ER stress and the consequent Unfolded Protein Response (UPR) while it rescues the diaphragmatic weakness by improving ER/mitochondria contacts, calcium dynamics, and OXPHOS. Importantly, treatments of SEPN1 knock out mice with the chemical chaperone tauroursodeoxycholic acid (TUDCA) mimic the results of ERO1 loss improving calcium dynamics, OXPHOS, ER/mitochondria contacts, thereby rescuing diaphragmatic weakness as well. In addition, TUDCA-treated SEPN1-RM patients-derived myoblasts show a dynamic dose-dependent increase in ATP levels under ER stress conditions suggesting improved mitochondrial function. Thus, our findings point to the ERO1 axis in the pathogenesis of SEPN1-RM thereby impinging on MAMs and mitochondria bioenergetics and recall for the efficacy of a pharmacology therapy with ad hoc ER stress/ERO1 inhibitors for SEPN1-RM.

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

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