Neurometabolic Diseases Lab

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Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Qian Zhang, Paul Bastard, Zhiyong Liu, Jérémie Le Pen, Marcela Moncada-Velez, Jie Chen, Masato Ogishi, Ira K. D. Sabli,
Stephanie Hodeib, Cecilia Korol, Jérémie Rosain, Kaya Bilguvar, Junqiang Ye, Alexandre Bolze, Benedetta Bigio, Rui Yang, Andrés
Augusto Arias, Qinhua Zhou, Yu Zhang, Fanny Onodi, Sarantis Korniotis, Léa Karpf, Quentin Philippot, Marwa Chbihi, Lucie
Bonnet-Madin, Karim Dorgham, Nikaïa Smith, William M. Schneider, Brandon S. Razooky, Hans-Heinrich Hoffmann, Eleftherios
Michailidis, Leen Moens, Ji Eun Han, Lazaro Lorenzo, Lucy Bizien, Philip Meade, Anna-Lena Neehus, Aileen Camille Ugurbil,
Aurélien Corneau, Gaspard Kerner, Peng Zhang, Franck Rapaport, Yoann Seeleuthner, Jeremy Manry, Cecile Masson, Yohann
Schmitt, Agatha Schlüter, Tom Le Voyer, Taushif Khan, Juan Li, Jacques Fellay, Lucie Roussel, Mohammad Shahrooei,
Mohammed F. Alosaimi, Davood Mansouri, Haya Al-Saud, Fahd Al-Mulla, Feras Almourfi, Saleh Zaid Al-Muhsen, Fahad Alsohime,
Saeed Al Turki, Rana Hasanato, Diederik van de Beek, Andrea Biondi, Laura Rachele Bettini, Mariella D'Angio, Paolo Bonfanti,
Luisa Imberti, Alessandra Sottini, Simone Paghera, Eugenia Quiros-Roldan, Camillo Rossi, Andrew J. Oler, Miranda F. Tompkins,
Camille Alba, Isabelle Vandernoot, Jean-Christophe Goffard, Guillaume Smits, Isabelle Migeotte, Filomeen Haerynck, Pere
Soler-Palacin, Andrea Martin-Nalda, Roger Colobran, Pierre-Emmanuel Morange, Sevgi Keles, Fatma Çölkesen, Tayfun Ozcelik,
Kadriye Kart Yasar, Sevtap Senoglu, Semsi Nur Karabela, Carlos Rodríguez Gallego, Giuseppe Novelli, Sami Hraiech, Yacine
Tandjaoui-Lambiotte, Xavier Duval, Cédric Laouénan, COVID-STORM Clinicians, COVID Clinicians, Imagine COVID Group, French
COVID Cohort Study Group, CoV-Contact Cohort, Amsterdam UMC Covid-19, Biobank, COVID Human Genetic Effort,
NIAID-USUHS, TAGC COVID Immunity Group, Andrew L. Snow, Clifton L. Dalgard, Joshua Milner, Donald C. Vinh, Trine H.
Mogensen, Nico Marr, András N. Spaan, Bertrand Boisson, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Anne Puel, Michael
Ciancanelli, Isabelle Meyts, Tom Maniatis, Vassili Soumelis, Ali Amara, Michel Nussenzweig, Adolfo García-Sastre, Florian
Krammer, Aurora Pujol, Darragh Duffy, Richard Lifton, Shen-Ying Zhang, Guy Gorochov, Vivien Béziat, Emmanuelle Jouanguy,
Vanessa Sancho-Shimizu, Charles M. Rice, Laurent Abel, Luigi D. Notarangelo, Aurélie Cobat, Helen C. Su and Jean-Laurent

Science. 2020 Sep 24;eabd4570. doi: 10.1126/science.abd4570. Online ahead of print

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection

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Last Updated on Thursday, 11 March 2021 13:41
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Epigenomic signature of adrenoleukodystrophy predicts compromised oligodendrocyte differentiation


Schlüter A, Sandoval J, Fourcade S, Díaz-Lagares A, Ruiz M, Casaccia P, Esteller M, Pujol A .

Brain Pathol. 2018 Feb 24. PMID: 29476661. doi: 10.1111/bpa.12595. [Epub ahead of print]

Epigenomic changes may either cause disease or modulate its expressivity, adding a layer of complexity to mendelian diseases. X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic condition exhibiting discordant phenotypes, ranging from a childhood cerebral inflammatory demyelination (cALD) to an adult-onset mild axonopathy in spinal cords (AMN). The AMN form may occur with superimposed inflammatory brain demyelination (cAMN). All patients harbor loss of function mutations in the ABCD1 peroxisomal transporter of very-long chain fatty acids. The factors that account for the lack of genotype-phenotype correlation, even within the same family, remain largely unknown. To gain insight into this matter, here we compared the genome-wide DNA methylation profiles of morphologically intact frontal white matter areas of children affected by cALD with adult cAMN patients, including male controls in the same age group. We identified a common methylomic signature between the two phenotypes, comprising (i) hypermethylation of genes harboring the H3K27me3 mark at promoter regions, (ii) hypermethylation of genes with major roles in oligodendrocyte differentiation such as MBP, CNP, MOG and PLP1 and (iii) hypomethylation of immune-associated genes such as IFITM1 and CD59. Moreover, we found increased hypermethylation in CpGs of genes involved in oligodendrocyte differentiation, and also in genes with H3K27me3 marks in their promoter regions in cALD compared with cAMN, correlating with transcriptional and translational changes. Further, using a penalized logistic regression model, we identified the combined methylation levels of SPG20, UNC45A and COL9A3 and also, the combined expression levels of ID4 and MYRF to be good markers capable of discriminating childhood from adult inflammatory phenotypes. We thus propose the hypothesis that an epigenetically controlled, altered transcriptional program may drive an impaired oligodendrocyte differentiation and aberrant immune activation in X-ALD patients. These results shed light into disease pathomechanisms and uncover putative biomarkers of interest for prognosis and phenotypic stratification.

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Last Updated on Thursday, 11 March 2021 13:49

We open Human Molecular Genetics in August!

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Cover: Proposed molecular mechanism for mitochondrial impairment in X-linked adrenoleukodystrophy. As C26:0 cannot enter peroxisomes for degradation due to the loss of the peroxisomal transporter ABCD1, it accumulates intracellularly affecting the inner mitochondrial membrane impermeability by unknown mechanisms. This alteration may allow a proton flux into the matrix decreasing Δψm, together with a certain extent of electron leakage promoting ROS formation. These ROS oxidise mitochondrial proteins of TCA cycle and OXPHOS, leading to impaired bioenergetics and respiration, and also oxidise mtDNA, contributing to a devil cycle of mitochondrial dysfunction and ultimately, cell demise. See article by López-Erauskin et al., pp. 3296–3305.

Last Updated on Sunday, 04 October 2020 11:19

Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy. Brain. 2013 Aug;136(Pt 8):2432-43.

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Morató L, Galino J, Ruiz M, Calingasan NY, Starkov AA, Dumont M, Naudí A, Martínez JJ, Aubourg P, Portero-Otín M, Pamplona R, Galea E, Beal MF, Ferrer I, Fourcade S, Pujol A. Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy. Brain. 2013 Aug;136(Pt 8):2432-43.

X-linked adrenoleukodystrophy is a neurometabolic disorder caused by inactivation of the peroxisomal ABCD1 transporter of very long-chain fatty acids. In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Increasing evidence indicates that oxidative stress and bioenergetic failure play major roles in the pathogenesis of X-linked adrenoleukodystrophy. In this study, we aimed to evaluate whether mitochondrial biogenesis is affected in X-linked adrenoleukodystrophy. We demonstrated that Abcd1 null mice show reduced mitochondrial DNA concomitant with downregulation of mitochondrial biogenesis pathway driven by PGC-1α/PPARγ and reduced expression of mitochondrial proteins cytochrome c, NDUFB8 and VDAC. Moreover, we show that the oral administration of pioglitazone, an agonist of PPARγ, restored mitochondrial content and expression of master regulators of biogenesis, neutralized oxidative damage to proteins and DNA, and reversed bioenergetic failure in terms of ATP levels, NAD+/NADH ratios, pyruvate kinase and glutathione reductase activities. Most importantly, the treatment halted locomotor disability and axonal damage in X-linked adrenoleukodystrophy mice. These results lend support to the use of pioglitazone in clinical trials with patients with adrenomyeloneuropathy and reveal novel molecular mechanisms of action of pioglitazone in neurodegeneration. Future studies should address the effects of this anti-diabetic drug on other axonopathies in which oxidative stress and mitochondrial dysfunction are contributing factors.

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&Scientific Commentary by Carlos Moraes, Brain July 10 2013 doi:10.1093/brain/awt189. Pdf: pdf button
&Scientific Commentary by Nature Reviews Neurology. Research Highlight. July 16 2013 doi:10.1038/nrneurol.2013.141. Pdf: pdf button

Last Updated on Thursday, 11 March 2021 13:48

Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: A paradigm for multifactorial neurodegenerative diseases? Biochim Biophys Acta. 2012 Sep;1822(9):1475-88.

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Galea E, Launay N, Portero-Otin M, Ruiz M, Pamplona R, Aubourg P, Ferrer I, Pujol A. Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: A paradigm for multifactorial neurodegenerative diseases? Biochim Biophys Acta. 2012 Sep;1822(9):1475-88.

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder expressed as four disease variants characterized by adrenal insufficiency and graded damage in the nervous system. X-ALD is caused by a loss of function of the peroxisomal ABCD1 fatty-acid transporter, resulting in the accumulation of very long chain fatty acids (VLCFA) in the organs and plasma, which have potentially toxic effects in CNS and adrenal glands. We have recently shown that treatment with a combination of antioxidants containing α-tocopherol, N-acetyl-cysteine and α-lipoic acid reversed oxidative damage and energetic failure, together with the axonal degeneration and locomotor impairment displayed by Abcd1 null mice, the animal model of X-ALD. This is the first direct demonstration that oxidative stress, which is a hallmark not only of X-ALD, but also of other neurodegenerative processes, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), contributes to axonal damage. The purpose of this review is, first, to discuss the molecular and cellular underpinnings of VLCFA-induced oxidative stress, and how it interacts with energy metabolism and/or inflammation to generate a complex syndrome wherein multiple factors are contributing. Particular attention will be paid to the dysregulation of redox homeostasis by the interplay between peroxisomes and mitochondria. Second, we will extend this analysis to the aforementioned neurodegenerative diseases with the aim of defining differences as well as the existence of a core pathogenic mechanism that would justify the exchange of therapeutic opportunities among these pathologies. This article is part of a Special Issue entitled: Metabolic functions and biogenesis of peroxisomes in health and disease.

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&Featured by Faculty of 1000 (Professor Mike Johnston, Kennedy Krieger Institute and John Hopkins University Hospital).

Last Updated on Thursday, 11 March 2021 13:48
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