Publications by authors named "Agatha Schlüter"

41 Publications

Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.

EBioMedicine 2021 Mar 26;65:103246. Epub 2021 Feb 26.

Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy.

Background: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome.

Methods: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects.

Findings: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing).

Interpretation: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats.

Funding: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2021.103246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908850PMC
March 2021

DLG4-related synaptopathy: a new rare brain disorder.

Authors:
Agustí Rodríguez-Palmero Melissa Maria Boerrigter David Gómez-Andrés Kimberly A Aldinger Íñigo Marcos-Alcalde Bernt Popp David B Everman Alysia Kern Lovgren Stephanie Arpin Vahid Bahrambeigi Gea Beunders Anne-Marie Bisgaard V A Bjerregaard Ange-Line Bruel Thomas D Challman Benjamin Cogné Christine Coubes Stella A de Man Anne-Sophie Denommé-Pichon Thomas J Dye Frances Elmslie Lars Feuk Sixto García-Miñaúr Tracy Gertler Elisa Giorgio Nicolas Gruchy Tobias B Haack Chad R Haldeman-Englert Bjørn Ivar Haukanes Juliane Hoyer Anna C E Hurst Bertrand Isidor Maria Johansson Soller Sulagna Kushary Malin Kvarnung Yuval E Landau Kathleen A Leppig Anna Lindstrand Lotte Kleinendorst Alex MacKenzie Giorgia Mandrile Bryce A Mendelsohn Setareh Moghadasi Jenny E Morton Sebastien Moutton Amelie J Müller Melanie O'Leary Marta Pacio-Míguez Maria Palomares-Bralo Sumit Parikh Rolph Pfundt Ben Pode-Shakked Anita Rauch Elena Repnikova Anya Revah-Politi Meredith J Ross Claudia A L Ruivenkamp Elisabeth Sarrazin Juliann M Savatt Agatha Schlüter Bitten Schönewolf-Greulich Zohra Shad Charles Shaw-Smith Joseph T Shieh Motti Shohat Stephanie Spranger Heidi Thiese Frederic Tran Mau-Them Bregje van Bon Ineke van de Burgt Ingrid M B H van de Laar Esmée van Drie Mieke M van Haelst Conny M van Ravenswaaij-Arts Edgard Verdura Antonio Vitobello Stephan Waldmüller Sharon Whiting Christiane Zweier Carlos E Prada Bert B A de Vries William B Dobyns Simone F Reiter Paulino Gómez-Puertas Aurora Pujol Zeynep Tümer

Genet Med 2021 Feb 17. Epub 2021 Feb 17.

Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Purpose: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.

Methods: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.

Results: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.

Conclusion: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-01075-9DOI Listing
February 2021

A novel hypomorphic splice variant in EIF2B5 gene is associated with mild ovarioleukodystrophy.

Ann Clin Transl Neurol 2020 09 15;7(9):1574-1579. Epub 2020 Aug 15.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908, Spain.

Objective: To identify the genetic cause in an adult ovarioleukodystrophy patient resistant to diagnosis.

Methods: We applied whole-exome sequencing (WES) to a vanishing white matter disease patient associated with premature ovarian failure at 26 years of age. We functionally tested an intronic variant by RT-PCR on patient's peripheral blood mononuclear cells (PBMC) and by minigene splicing assay.

Results: WES analysis identified two novel variants in the EIF2B5 gene: c.725A > G (p.Tyr242Cys) and an intronic noncanonical mutation (c.1156 + 13G>A). This intronic mutation resulted into generation of various isoforms both in patient's PBMC and in the minigene splicing assay, showing that ~20% residual wild-type isoform is still expressed by the intronic-mutated allele alone, concordant with an hypomorphic effect of this variant.

Conclusion: We report two novel variants in EIF2B5, one of them a noncanonical intronic splice variant, located at a +13 intronic position. This position is mutated only in 0.05% of ClinVar intronic mutations described so far. Furthermore, we illustrate how minigene splicing assay may be advantageous when validating splice-altering variants, in this case highlighting the coexistence of wild-type and mutated forms, probably explaining this patient's milder, late-onset phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480926PMC
September 2020

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

Authors:
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 Şemsi Nur Karabela Carlos Rodríguez-Gallego Giuseppe Novelli Sami Hraiech Yacine Tandjaoui-Lambiotte Xavier Duval Cédric Laouénan Andrew L Snow Clifton L Dalgard Joshua D Milner Donald C Vinh Trine H Mogensen Nico Marr András N Spaan Bertrand Boisson Stéphanie Boisson-Dupuis Jacinta Bustamante Anne Puel Michael J Ciancanelli Isabelle Meyts Tom Maniatis Vassili Soumelis Ali Amara Michel Nussenzweig Adolfo García-Sastre Florian Krammer Aurora Pujol Darragh Duffy Richard P 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 Jean-Laurent Casanova

Science 2020 10 24;370(6515). Epub 2020 Sep 24.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (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 Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (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 defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abd4570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857407PMC
October 2020

Expanding the clinical and genetic spectrum of PCYT2-related disorders.

Brain 2020 09;143(9):e76

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa229DOI Listing
September 2020

Case Report: Benign Infantile Seizures Temporally Associated With COVID-19.

Front Pediatr 2020 6;8:507. Epub 2020 Aug 6.

NavarraBioMed and IdiSNA, Health Research Institute, Pamplona, Spain.

Non-febrile illness seizures may present in previously healthy children as afebrile seizures associated with minor infections, such as mild gastroenteritis or respiratory tract infections, and are linked to a genetic predisposition. For the novel human coronavirus SARS-CoV-2, causing COVID-19, fever, cough, and gastrointestinal complaints are the most common symptoms in children, and a hyperimmune response may be present. No detailed temporally associated neurological complications have been documented in pediatric case series so far. We present the case of a 3-months-old girl with non-febrile repeated seizures in a COVID-19 family setting. The infant started with a mild fever and cough that lasted for 2 days. At day 6 from onset, the girl presented with two focal motor seizures with impaired consciousness and awareness. All investigations ruled out signs of meningo-encephalitis or active epilepsy, including normal electroencephalogram and cerebral magnetic resonance imaging. PCR from nasal and throat swabs was positive for SARS-CoV-2. Remarkably, blood ferritin and D-dimer levels were increased. At day 9, the infant presented another afebrile motor seizure, and levetiracetam dose was modified there was a favorable response within 3 months of the follow-up. Much interest has been raised with regards to host genetic determinants to disease severity and susceptibility to COVID-19. We thus performed whole exome sequencing, revealing a pathogenic frameshift mutation in the PRRT2 gene in both the mother and the infant. The mother had presented two late infantile febrile convulsions with normal outcome afterwards. The hyperimmune response described in adult cases with COVID-19 can be seen in infants, even in the absence of respiratory symptoms. Moreover, COVID-19 may present in infants as non-febrile seizures, triggering early onset seizures in infants with a genetic predisposition. In this pandemic situation, precision medicine using massive sequencing can shed light on underlying molecular mechanisms driving the host response to COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2020.00507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423871PMC
August 2020

High-dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy.

Brain Pathol 2020 09 7;30(5):945-963. Epub 2020 Jul 7.

Neurometabolic Diseases Laboratory, IDIBELL, Barcelona, Spain.

Biotin is an essential cofactor for carboxylases that regulates the energy metabolism. Recently, high-dose pharmaceutical-grade biotin (MD1003) was shown to improve clinical parameters in a subset of patients with chronic progressive multiple sclerosis. To gain insight into the mechanisms of action, we investigated the efficacy of high-dose biotin in a genetic model of chronic axonopathy caused by oxidative damage and bioenergetic failure, the Abcd1 mouse model of adrenomyeloneuropathy. High-dose biotin restored redox homeostasis driven by NRF-2, mitochondria biogenesis and ATP levels, and reversed axonal demise and locomotor impairment. Moreover, we uncovered a concerted dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord likely driven by aberrant SREBP-1c/mTORC1signaling. This resulted in increased triglyceride levels and lipid droplets in motor neurons. High-dose biotin normalized the hyperactivation of mTORC1, thus restoring lipid homeostasis. These results shed light into the mechanism of action of high-dose biotin of relevance for neurodegenerative and metabolic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12869DOI Listing
September 2020

HNRNPH1-related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome.

Clin Genet 2020 07 15;98(1):91-98. Epub 2020 May 15.

Department of Human and Molecular Genetics, Clinical Genetics Services, VCU Health, Richmond, Virginia, USA.

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13765DOI Listing
July 2020

The peroxisomal fatty acid transporter ABCD1/PMP-4 is required in the C. elegans hypodermis for axonal maintenance: A worm model for adrenoleukodystrophy.

Free Radic Biol Med 2020 05 1;152:797-809. Epub 2020 Feb 1.

Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Spain; CIBERER U759, Center for Biomedical Research on Rare Diseases, Spain; ICREA (Institució Catalana de Recerca i Estudis Avançats), Barcelona, Spain. Electronic address:

Adrenoleukodystrophy is a neurometabolic disorder caused by a defective peroxisomal ABCD1 transporter of very long-chain fatty acids (VLCFAs). Its pathogenesis is incompletely understood. Here we characterize a nematode model of X-ALD with loss of the pmp-4 gene, the worm orthologue of ABCD1. These mutants recapitulate the hallmarks of X-ALD: i) VLCFAs accumulation and impaired mitochondrial redox homeostasis and ii) axonal damage coupled to locomotor dysfunction. Furthermore, we identify a novel role for PMP-4 in modulating lipid droplet dynamics. Importantly, we show that the mitochondria targeted antioxidant MitoQ normalizes lipid droplets size, and prevents axonal degeneration and locomotor disability, highlighting its therapeutic potential. Moreover, PMP-4 acting solely in the hypodermis rescues axonal and locomotion abnormalities, suggesting a myelin-like role for the hypodermis in providing essential peroxisomal functions for the nematode nervous system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.freeradbiomed.2020.01.177DOI Listing
May 2020

A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases.

Ann Clin Transl Neurol 2020 01 18;7(1):105-111. Epub 2019 Dec 18.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

Objective: To identify causative mutations in a patient affected by ataxia and spastic paraplegia.

Methods: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) were performed using patient's DNA sample. RT-PCR and cDNA Sanger sequencing were performed on RNA extracted from patient's fibroblasts, as well as western blot.

Results: A novel missense variant in SPG7 (c.2195T> C; p.Leu732Pro) was first found by whole-exome sequencing (WES), while the second, also unreported, deep intronic variant (c.286 + 853A>G) was identified by whole-genome sequencing (WGS). RT-PCR confirmed the in silico predictions showing that this variant activated a cryptic splice site, inducing the inclusion of a pseudoexon into the mRNA sequence, which encoded a premature stop codon. Western blot showed decreased SPG7 levels in patient's fibroblasts.

Interpretation: Identification of a deep intronic variant in SPG7, which could only have been detected by performing WGS, led to a diagnosis in this HSP patient. This case challenges the notion of an autosomal dominant inheritance for SPG7, and illustrates the importance of performing WGS subsequently or alternatively to WES to find additional mutations, especially in patients carrying one variant in a gene causing a predominantly autosomal recessive disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.50967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952318PMC
January 2020

Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia.

Hum Mutat 2020 03 25;41(3):632-640. Epub 2019 Nov 25.

Department of Molecular and Human Genetics, Faculty of Medicine, Baylor College of Medicine, Houston, Texas.

Hereditary spastic paraplegia (HSP) is a group of disorders with predominant symptoms of lower-extremity weakness and spasticity. Despite the delineation of numerous genetic causes of HSP, a significant portion of individuals with HSP remain molecularly undiagnosed. Through exome sequencing, we identified five unrelated families with childhood-onset nonsyndromic HSP, all presenting with progressive spastic gait, leg clonus, and toe walking starting from 7 to 8 years old. A recurrent two-base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense-mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified in this study are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant-negative effect on the normal function of the endosome-specific endosomal sorting complexes required for the transport-I complex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23950DOI Listing
March 2020

Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia.

J Med Genet 2020 02 5;57(2):132-137. Epub 2019 Oct 5.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain

Background: Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in , encoding the voltage-gated K channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as events.

Methods: A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings.

Results: WES revealed a homozygous variant (p.Val368Leu) in , involving a conserved residue in the pore domain, close to the selectivity signature sequence for K ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures.

Conclusion: This newly identified variant is the first to be reported to act in a recessive mode of inheritance in . These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2019-106373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029237PMC
February 2020

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.

Mov Disord 2019 10 21;34(10):1547-1561. Epub 2019 Aug 21.

Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.

Background: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA.

Objectives: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients.

Methods: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction.

Results: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001).

Conclusions: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.27812DOI Listing
October 2019

Clinical presentation and proteomic signature of patients with TANGO2 mutations.

J Inherit Metab Dis 2020 03 13;43(2):297-308. Epub 2019 Aug 13.

Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q (CoQ ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jimd.12156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078914PMC
March 2020

Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study.

Neurotherapeutics 2019 10;16(4):1167-1182

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, Hospital Duran i Reynals, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.

X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-019-00735-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985062PMC
October 2019

A novel mutation in the gene expands the phenotype of Alexander disease.

J Med Genet 2019 12 19;56(12):846-849. Epub 2019 Apr 19.

Neurometabolic Diseases Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Catalonia, Spain

Background: Alexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in . Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist.

Methods: A family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by whole exome sequencing (WES). A candidate variant was functionally tested in an astrocytoma cell line.

Results: The novel variant in (Glial Fibrillary Acidic Protein) N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterised so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models.

Conclusion: We suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander disease type II, probably associated with alternative pathogenic mechanisms, that is, astrocyte enlargement. analysis should be considered in adult-onset neurological presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2018-105959DOI Listing
December 2019

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

J Clin Invest 2019 03 11;129(3):1240-1256. Epub 2019 Feb 11.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI123959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391109PMC
March 2019

Epigenomic signature of adrenoleukodystrophy predicts compromised oligodendrocyte differentiation.

Brain Pathol 2018 11 10;28(6):902-919. Epub 2018 Apr 10.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857458PMC
November 2018

Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder.

Am J Hum Genet 2017 Dec;101(6):965-976

Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. Electronic address:

Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3' untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3' UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2017.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812895PMC
December 2017

Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.

Clin Pharmacol Ther 2018 04 3;103(4):712-721. Epub 2017 Nov 3.

Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10 ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828950PMC
April 2018

Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families.

Neurology 2016 Jul 17;87(2):186-91. Epub 2016 Jun 17.

From the Institute of Medical Genetics and Applied Genomics (A.S.S., S.B.-W., K.S., O.R., P.B.) and Department of Neurology and Hertie Institute for Clinical Brain Research (T.W.R., R.S., L.S.), University of Tübingen; German Center of Neurodegenerative Diseases (DZNE) (T.W.R., R.S.), Tübingen, Germany; Imprinting and Cancer Group (D.M.), Cancer Epigenetic and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain; Department of Neuropediatrics (M.D.-N.), Tübingen University School of Medicine; CeGaT GmbH (K.H.), Tübingen, Germany; Neurometabolic Diseases Laboratory (A.S., M.R., A.P.), Institut d'Investigació Biomedica de Bellvitge IDIBELL, Hospital Duran i Reynals, Barcelona; Centre for Biomedical Research on Rare Diseases (CIBERER) (A.S., M.R., A.P.), Institute Carlos III, Madrid; Catalan Institution for Research and Advanced Studies (ICREA) (A.P.), Barcelona, Spain; and Hussman Institute for Human Genomics (S.Z., R.S.), University of Miami Miller School of Medicine, FL.

Objective: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias.

Method: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes.

Results: Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling.

Conclusion: UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000002843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940069PMC
July 2016

Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury.

Glia 2016 May 16;64(5):853-74. Epub 2016 Feb 16.

Institut De Neurociències and Unitat De Bioquímica, Facultat De Medicina, Universitat Autònoma De Barcelona, Bellaterra, Barcelona, 08193, Spain.

The clinical challenge in acute injury as in traumatic brain injury (TBI) is to halt the delayed neuronal loss that occurs hours and days after the insult. Here we report that the activation of CREB-dependent transcription in reactive astrocytes prevents secondary injury in cerebral cortex after experimental TBI. The study was performed in a novel bitransgenic mouse in which a constitutively active CREB, VP16-CREB, was targeted to astrocytes with the Tet-Off system. Using histochemistry, qPCR, and gene profiling we found less neuronal death and damage, reduced macrophage infiltration, preserved mitochondria, and rescued expression of genes related to mitochondrial metabolism in bitransgenic mice as compared to wild type littermates. Finally, with meta-analyses using publicly available databases we identified a core set of VP16-CREB candidate target genes that may account for the neuroprotective effect. Enhancing CREB activity in astrocytes thus emerges as a novel avenue in acute brain post-injury therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/glia.22969DOI Listing
May 2016

Altered glycolipid and glycerophospholipid signaling drive inflammatory cascades in adrenomyeloneuropathy.

Hum Mol Genet 2015 Dec 14;24(24):6861-76. Epub 2015 Sep 14.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Institute of Neuropathology, University of Barcelona, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Center for Biomedical Research on Rare Diseases (CIBERER), Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain

X-linked adrenomyeloneuropathy (AMN) is an inherited neurometabolic disorder caused by malfunction of the ABCD1 gene, characterized by slowly progressing spastic paraplegia affecting corticospinal tracts, and adrenal insufficiency. AMN is the most common phenotypic manifestation of adrenoleukodystrophy (X-ALD). In some cases, an inflammatory cerebral demyelination occurs associated to poor prognosis in cerebral AMN (cAMN). Though ABCD1 codes for a peroxisomal transporter of very long-chain fatty acids, the molecular mechanisms that govern disease onset and progression, or its transformation to a cerebral, inflammatory demyelinating form, remain largely unknown. Here we used an integrated -omics approach to identify novel biomarkers and altered network dynamic characteristic of, and possibly driving, the disease. We combined an untargeted metabolome assay of plasma and peripheral blood mononuclear cells (PBMC) of AMN patients, which used liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (LC-Q-TOF), with a functional genomics analysis of spinal cords of Abcd1(-) mouse. The results uncovered altered nodes in lipid-driven proinflammatory cascades, such as glycosphingolipid and glycerophospholipid synthesis, governed by the β-1,4-galactosyltransferase (B4GALT6), the phospholipase 2γ (PLA2G4C) and the choline/ethanolamine phosphotransferase (CEPT1) enzymes. Confirmatory investigations revealed a non-classic, inflammatory profile, consisting on the one hand of raised plasma levels of several eicosanoids derived from arachidonic acid through PLA2G4C activity, together with also the proinflammatory cytokines IL6, IL8, MCP-1 and tumor necrosis factor-α. In contrast, we detected a more protective, Th2-shifted response in PBMC. Thus, our findings illustrate a previously unreported connection between ABCD1 dysfunction, glyco- and glycerolipid-driven inflammatory signaling and a fine-tuned inflammatory response underlying a disease considered non-inflammatory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddv375DOI Listing
December 2015

Neuroinflammatory signals in Alzheimer disease and APP/PS1 transgenic mice: correlations with plaques, tangles, and oligomeric species.

J Neuropathol Exp Neurol 2015 Apr;74(4):319-44

From the Institut de Neuropatologia, Institut d'Investigació Biomèdica de Bellvitge-Hospital Universitari de Bellvitge (IL-G, EA, PG-E, BA, FL, MC, JM, AP, IF); Universitat de Barcelona (IF); and Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (AS, AP), Hospitalet de Llobregat; Catalan Institution for Research and Advanced Studies (AP), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (IF) and Center for Biomedical Research on Rare Diseases (AS, AP), Madrid; and Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida, Lleida (MP-O, RP), Spain; and Section Neuroscience, Department of Psychology, Sapienza University of Rome (AF); and European Center for Brain Research/IRCCS Santa Lucia Foundation (AF), Rome, Italy.

To understand neuroinflammation-related gene regulation during normal aging and in sporadic Alzheimer disease (sAD), we performed functional genomics analysis and analyzed messenger RNA (mRNA) expression by quantitative reverse transcription-polymerase chain reaction of 22 genes involved in neuroinflammation-like responses in the cerebral cortex of wild-type and APP/PS1 transgenic mice. For direct comparisons, mRNA expression of 18 of the same genes was then analyzed in the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 of middle-aged human subjects lacking Alzheimer disease-related pathology and in older subjects with sAD pathology covering Stages I-II/0(A), III-IV/A-B, and V-VI/C of Braak and Braak classification. Modifications of cytokine and immune mediator mRNA expression were found with normal aging in wild-type mice and in middle-aged individuals and patients with early stages of sAD-related pathology; these were accompanied by increased protein expression of certain mediators in ramified microglia. In APP/PS1 mice, inflammatory changes coincided with β-amyloid (Aβ) deposition; increased levels of soluble oligomers paralleled the modified mRNA expression of cytokines and mediators in wild-type mice. In patients with sAD, regulation was stage- and region-dependent and not merely acceleration and exacerbation of mRNA regulation with aging. Gene regulation at first stages of AD was not related to hyperphosphorylated tau deposition in neurofibrillary tangles, Aβ plaque burden, concentration of Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), or fibrillar Aβ linked to membranes but rather to increased levels of soluble oligomers. Thus, species differences and region- and stage-dependent inflammatory responses in sAD, particularly at the initial stages, indicate the need to identify new anti-inflammatory compounds with specific molecular therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NEN.0000000000000176DOI Listing
April 2015

Deregulation of purine metabolism in Alzheimer's disease.

Neurobiol Aging 2015 Jan 8;36(1):68-80. Epub 2014 Aug 8.

Institute of Neuropathology, Bellvitge University Hospital-Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Spain; University of Barcelona, Bellvitge Campus, L'Hospitalet de Llobregat, Spain; Centre for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Madrid, Spain. Electronic address:

The neuroprotective role of adenosine and the deregulation of adenosine receptors in Alzheimer's disease (AD) have been extensively studied in recent years. However, little is known about the involvement of purine metabolism in AD. We started by analyzing gene expression in the entorhinal cortex of human controls and AD cases with whole-transcript expression arrays. Once we identified deregulation of the cluster purine metabolism, messenger RNA expression levels of 23 purine metabolism genes were analyzed with qRT-PCR in the entorhinal cortex, frontal cortex area 8, and precuneus at stages I-II, III-IV, and V-VI of Braak and Braak and controls. APRT, DGUOK, POLR3B, ENTPD3, AK5, NME1, NME3, NME5, NME7, and ENTPD2 messenger RNAs were deregulated, with regional variations, in AD cases when compared with controls. In addition, liquid chromatography mass spectrometry based metabolomics in the entorhinal cortex identified altered levels of dGMP, glycine, xanthosine, inosine diphosphate, guanine, and deoxyguanosine, all implicated in this pathway. Our results indicate stage- and region-dependent deregulation of purine metabolism in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2014.08.004DOI Listing
January 2015

ABCD2 alters peroxisome proliferator-activated receptor α signaling in vitro, but does not impair responses to fenofibrate therapy in a mouse model of diet-induced obesity.

Mol Pharmacol 2014 Nov 14;86(5):505-13. Epub 2014 Aug 14.

Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.)

Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) α ligand that has been widely used as a lipid-lowering agent in the treatment of hypertriglyceridemia. ABCD2 (D2) is a peroxisomal long-chain acyl-CoA transporter that is highly induced by fenofibrate in the livers of mice. To determine whether D2 is a modifier of fibrate responses, wild-type and D2-deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPARα signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that knockdown of D2 modified genomic responses to fibrate treatment. We next evaluated the impact of D2 on effects of fibrates in a mouse model of diet-induced obesity. Fenofibrate treatment opposed the development of obesity, hypertriglyceridemia, and insulin resistance. However, these effects were unaffected by D2 genotype. We concluded that D2 can modulate genomic responses to fibrates, but that these effects are not sufficiently robust to alter the effects of fibrates on diet-induced obesity phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/mol.114.092742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201141PMC
November 2014

Functional genomics reveals dysregulation of cortical olfactory receptors in Parkinson disease: novel putative chemoreceptors in the human brain.

J Neuropathol Exp Neurol 2013 Jun;72(6):524-39

Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.

Parkinson disease (PD) is no longer considered a complex motor disorder but rather a systemic disease with variable nonmotor deficits that may include impaired olfaction, depression, mood and sleep disorders, and altered cortical function. Increasing evidence indicates that multiple metabolic defects occur in regions outside the substantia nigra, including the cerebral cortex, even at premotor stages of the disease. We investigated changes in gene expression in the frontal cortex in PD patient brains using a transcriptomics approach. Functional genomics analysis indicated that cortical olfactory receptors (ORs) and taste receptors (TASRs) are altered in PD patients. Olfactory receptors OR2L13, OR1E1, OR2J3, OR52L1, and OR11H1 and taste receptors TAS2R5 and TAS2R50 were downregulated, but TAS2R10 and TAS2R13 were upregulated at premotor and parkinsonian stages in the frontal cortex area 8 in PD patient brains. Furthermore, we present novel evidence that, in addition to the ORs, obligate downstream components of OR function adenylyl cyclase 3 and olfactory G protein (Gαolf), OR transporters, receptor transporter proteins 1 and 2 and receptor expression enhancing protein 1, and OR xenobiotic removing UDP-glucuronosyltransferase 1 family polypeptide A6 are widely expressed in neurons of the cerebral cortex and other regions of the adult human brain. Together, these findings support the concept that ORs and TASRs in the cerebral cortex may have novel physiologic functions that are affected in PD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NEN.0b013e318294fd76DOI Listing
June 2013

Oxidative stress regulates the ubiquitin-proteasome system and immunoproteasome functioning in a mouse model of X-adrenoleukodystrophy.

Brain 2013 Mar;136(Pt 3):891-904

Neurometabolic Diseases Laboratory, Institute of Neuropathology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.

Oxidative damage is a pivotal aetiopathogenic factor in X-linked adrenoleukodystrophy. This is a neurometabolic disease characterized by the accumulation of very-long-chain fatty acids owing to the loss of function of the peroxisomal transporter Abcd1. Here, we used the X-linked adrenoleukodystrophy mouse model and patient's fibroblasts to detect malfunctioning of the ubiquitin-proteasome system resulting from the accumulation of oxidatively modified proteins, some involved in bioenergetic metabolism. Furthermore, the immunoproteasome machinery appears upregulated in response to oxidative stress, in the absence of overt inflammation. i-Proteasomes are recruited to mitochondria when fibroblasts are exposed to an excess of very-long-chain fatty acids in response to oxidative stress. Antioxidant treatment regulates proteasome expression, prevents i-proteasome induction and translocation of i-proteasomes to mitochondria. Our findings support a key role of i-proteasomes in quality control in mitochondria during oxidative damage in X-linked adrenoleukodystrophy, and perhaps in other neurodegenerative conditions with similar pathogeneses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/aws370DOI Listing
March 2013