Article
Clinical Neurology
Fabio Antonaci, Sabrina Ravaglia, Gaetano S. Grieco, Stella Gagliardi, Cristina Cereda, Alfredo Costa
Summary: In cases of Familial Hemiplegic migraine type 2 caused by ATP1A2 gene mutations, there is a certain hereditary pattern and mild clinical manifestations. Further study on intra-familial variability and functional consequences of the channel protein may help clarify genotype-phenotype correlations.
JOURNAL OF HEADACHE AND PAIN
(2021)
Article
Clinical Neurology
Giuseppe Donato Mangano, Maria Rita Capizzi, Elide Mantuano, Liana Veneziano, Giuseppe Santangelo, Giuseppe Quatrosi, Rosaria Nardello, Vincenzo Raieli
Summary: The aim of this study was to describe a cohort of pediatric patients with genetically confirmed familial hemiplegic migraine (FHM). The knowledge of genotype-phenotype correlations may suggest prognostic factors associated with severe phenotypes. The study data show that most of our patients with early-onset FHM experienced infrequent and non-severe attacks, which improved over time.
Article
Clinical Neurology
Buse Rahime Hasirci Bayir, Kemal Tutkavul, Metin Eser, Betul Baykan
Summary: This study systematically reviewed the coexistence of epilepsy in patients with familial hemiplegic migraine, finding that mutations in all three or possibly four FHM genes can cause epilepsy, with the highest number of cases associated with epilepsy belonging to the ATP1A2 mutation. Drug-resistant forms of epilepsy are rare in these patients.
SEIZURE-EUROPEAN JOURNAL OF EPILEPSY
(2021)
Article
Multidisciplinary Sciences
Keiko Ikeda, Adriana A. Tienda, Fiona E. Harrison, Kiyoshi Kawakami
Summary: The study showed that the alpha 2 and alpha 3 subunits of Na+,K+-ATPase independently contribute to the ascorbic acid levels in the fetal brain, while the alpha 3 subunit plays a role in ascorbic acid transport in the adult basal ganglia and cerebellum. A decrease in ascorbic acid levels may affect neural network development and could be linked to the pathophysiology of ATP1A2- and ATP1A3-related neurologic disorders.
Review
Clinical Neurology
Philippe A. Salles, Ignacio F. Mata, Tobias Bruenger, Dennis Lal, Hubert H. Fernandez
Summary: The Na+/K+ ATPases are a critical part of cell membrane function, with the ATP1A3 gene encoding the α 3 isoform which is associated with neurological disorders. Pathogenic variants in this gene can lead to a range of symptoms, often presenting with acute onset and triggered episodes by fever or other factors.
FRONTIERS IN NEUROLOGY
(2021)
Article
Clinical Neurology
Yingji Li, Wenjing Tang, Li Kang, Shanshan Kong, Zhao Dong, Dengfa Zhao, Ruozhuo Liu, Shengyuan Yu
Summary: Mutations in ATP1A2 gene can lead to phenotypes ranging from pure FHM to FHM with epilepsy and intellectual disability due to varying degrees of deficits in the biochemical and electrophysiological properties of Na+/K+-ATPase. Mutations associated with intellectual disability result in severe impairment of Na+/K+-ATPase, while the presence of epilepsy or the type of epilepsy does not seem to affect the degree of pump function impairment.
JOURNAL OF HEADACHE AND PAIN
(2021)
Article
Clinical Neurology
Marina Romozzi, Guido Primiano, Eleonora Rollo, Lorena Travaglini, Paolo Calabresi, Serenella Servidei, Catello Vollono
Summary: Hemiplegic migraine is a rare form of migraine that can be sporadic or familial. A mutation in the CACNA1A gene, specifically the p.Thr501Met variant, was found in 12 out of 15 patients in a family, leading to familial hemiplegic migraine. The mutation can prevalently occur as hemiplegic migraine without significant cerebellar involvement.
JOURNAL OF HEADACHE AND PAIN
(2021)
Article
Neurosciences
Riffat Mehboob, Anna Marchenkova, Arn M. J. M. van den Maagdenberg, Andrea Nistri
Summary: In transgenic knock-in mice with the R192Q missense mutation linked to familial hemiplegic migraine type 1, upregulation of Na(V)1.7 channels in trigeminal sensory neurons was observed, leading to increased excitability and facilitated nociceptive signaling. Co-expression of Na(V)1.7 channels and P2X3 receptors in trigeminal ganglia may be relevant to explaining hypersensitivity to local stimuli in migraine pathophysiology.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Article
Clinical Neurology
David Fear, Misha Patel, Ramin Zand
Summary: Hemiplegic migraines are a heterogeneous disorder with genetic etiology, classified as sporadic or familial based on family history. MRI changes in Isotropic Diffusion Map (DWI) and Apparent Diffusion Coefficient (ADC) may assist in identifying cases of Hemiplegic Migraine, indicating transient changes throughout the course of an attack.
Article
Biochemistry & Molecular Biology
Inge C. M. Loonen, Isabelle Kohler, Mohan Ghorasaini, Martin Giera, Arn M. J. M. van den Maagdenberg, Oleg A. Mayboroda, Else A. Tolner
Summary: Metabolite levels in peripheral body fluids may be associated with attack features in migraine patients, indicating the potential of plasma metabolites as disease biomarkers. Lipid metabolic pathways were found to be affected by CSD, with transient increase in PGD2 and elevated levels of anti-inflammatory lipid mediators in wild-type mice after CSD. Monitoring peripheral changes in lipids could provide insights into central brain mechanisms related to migraine pathophysiology.
Article
Clinical Neurology
Filippo Manti, Mario Mastrangelo, Roberta Battini, Claudia Carducci, Carlotta Spagnoli, Carlo Fusco, Manuela Tolve, Carla Carducci, Vincenzo Leuzzi
Summary: Patients with AADCD exhibit intellectual disability and psychiatric disorders, along with movement disorders such as parkinsonism-dystonia, dysarthria, and oculogyric crises. CSF levels of 5-HIAA and HVA at diagnosis significantly impact adaptive behavior and executive function performance. Homozygous DDC pathogenetic variants are associated with lower CSF levels and higher Parkinson's disease rating scale scores.
PARKINSONISM & RELATED DISORDERS
(2022)
Article
Neurosciences
Alina Suleimanova, Max Talanov, Arn M. J. M. van den Maagdenberg, Rashid Giniatullin
Summary: Familial hemiplegic migraine type 3 (FHM3) is caused by gain-of-function mutations in the SCN1A gene, resulting in a dysfunction of Na(V)1.1 sodium channels. Computer modeling revealed that FHM3-mutated Na(V)1.1 channels contribute to abnormal nociceptive signaling in trigeminal pain mechanisms. Mutations leading to loss of Na(V)1.1 function reduce firing of trigeminal nerve fibers, while combined activation of P2X3 and 5-HT3 receptors in mutants results in prolonged and high-frequency spiking activity.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Article
Biology
Nicole A. Terpollili, Reinhard Dolp, Kai Waehner, Susanne M. Schwarzmaier, Elisabeth Rumbler, Boyan Todorov, Michel D. Ferrari, Arn M. J. M. van den Maagdenberg, Nikolaus Plesnila
Summary: Patients with familial hemiplegic migraine type 1 (FHM1) may have severe outcomes after head trauma, and this study found that mice carrying FHM1 mutations had worse histopathological and functional outcomes after traumatic brain injury (TBI), possibly due to increased cortical spreading depolarizations (CSDs) and seizure activity.
Article
Biochemistry & Molecular Biology
Elena Arystarkhova, Mads S. Toustrup-Jensen, Rikke Holm, Jae-Kyun Ko, Kyung Eun Lee, Polina Feschenko, Laurie J. Ozelius, Allison Brashear, Bente Vilsen, Kathleen J. Sweadner
Summary: ATP1A3 encodes the alpha 3 isoform of Na,K-ATPase and is expressed only in neurons. Mutations in this gene result in a variety of phenotypes, with specific syndromes associated with unique substitutions. The pathogenicity of the R756H mutation was tested in mammalian cells and found to have reduced turnover rate, altered ion affinity, and resistance to misfolding.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Cinthia R. Millan, Martina Francis, Nitesh Kumar Khandelwal, Valery F. Thompson, Tarjani M. Thaker, Thomas M. Tomasiak
Summary: The study reveals the important role of the GRD motif in coordinating domain rearrangements in the heterodimeric peptide transporter TmrAB, with disruption of this network leading to different functional consequences and hinting at intrinsic asymmetry in the transporter. These findings suggest a mechanism by which the GRD motifs help coordinate a transition to an outward open conformation, with each half of the transporter playing a different role in the conformational cycle of TmrAB.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Christian P. Roenn, Melody Li, Vivien R. Schack, Ian C. Forster, Rikke Holm, Mads S. Toustrup-Jensen, Jens P. Andersen, Steven Petrou, Bente Vilsen
JOURNAL OF BIOLOGICAL CHEMISTRY
(2019)
Article
Multidisciplinary Sciences
Francesco Tadini-Buoninsegni, Stine A. Mikkelsen, Louise S. Mogensen, Robert S. Molday, Jens Peter Andersen
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2019)
Article
Genetics & Heredity
Hanbin Choi, Jens P. Andersen, Robert S. Molday
Article
Multidisciplinary Sciences
Ryuta Kanai, Flemming Cornelius, Haruo Ogawa, Kanna Motoyama, Bente Vilsen, Chikashi Toyoshima
Summary: The sodium pump (Na+, K+-ATPase, NKA) is crucial for maintaining ion gradients across cell membranes, with cardiotonic steroids (CTSs) acting as specific inhibitors. Different structural features of CTSs result in diverse inhibitory properties, with crystal structures providing insights into their mechanism of action and potential for isoform specific targeting.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Maxwell M. G. Geurts, Johannes D. Clausen, Bertrand Arnou, Cedric Montigny, Guillaume Lenoir, Robin A. Corey, Christine Jaxel, Jesper V. Moller, Poul Nissen, Jens Peter Andersen, Marc le Maire, Maike Bublitz
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Virology
Vivien R. Schack, Litten Sorensen Rossen, Clara Christina Ekebjaerg, Katrine Kyd Holstein Thuesen, Bettina Bundgaard, Per Hollsberg
Summary: The genetic approach showed that CD46 is critical for infection by HHV-6A, while CD9 modulates infection by promoting CD46-dependent infection and impairing CD46-independent infection. HHV-6B appears to be more promiscuous and may use different entry mechanisms in various cells.
JOURNAL OF VIROLOGY
(2021)
Article
Biochemical Research Methods
Nicklas H. Staunstrup, Charlotte C. Petersen, Tina Fuglsang, Anna Starnawska, Ana Chernomorchenko, Per Qvist, Vivien R. Schack
Summary: This study compared two fluorescence-activated technologies for cell sorting from small input samples, finding that the mechanical valve-based Tyto instrument perturbed cells to a lesser extent and resulted in significantly higher proliferation potential of T-cells compared to the high pressure and electrostatic deflection-based Aria instrument.
Article
Virology
Litten Sorensen Rossen, Vivien R. Schack, Katrine Kyd Holstein Thuesen, Bettina Bundgaard, Per Hollsberg
Summary: CD46 is the receptor used by human herpesvirus 6A (HHV-6A) during infection of T cells, while also involved in infection of certain T cells by HHV-6B. CD46 has several isoforms, with HHV-6A preferring BC isoforms for endocytosis-mediated infection of T cells, and HHV-6B preferring C isoforms for fusion-from-without infection. The isoforms of CD46 may play a role in regulating host susceptibility to HHV-6A and HHV-6B infection.
JOURNAL OF VIROLOGY
(2022)
Article
Multidisciplinary Sciences
Ryuta Kanai, Flemming Cornelius, Bente Vilsen, Chikashi Toyoshima
Summary: Cryo-electron microscopy was used to study the structure of Na+, K+-ATPase and its variations. The results showed that different reaction states exhibited different biochemical characteristics, and the presence of Mg2+ ions in the transmembrane cation binding sites played a crucial role in the reactions. The binding mechanism of the new-generation cardiotonic steroids (CTSs) did not significantly affect the structure of NKA, and the phospholipid molecules were better resolved in the electron microscopy maps compared to X-ray structures.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Francesco Tadini-Buoninsegni, Stine A. Mikkelsen, Louise S. Mogensen, Rikke Holm, Robert S. Molday, Jens Peter Andersen
Summary: The study reveals the electrogenicity of ATP8A2 and its potential phospholipid translocation pathway involving residues with positively charged side chains.
Article
Physiology
Kerri Spontarelli, Daniel T. Infield, Hang N. Nielsen, Rikke Holm, Victoria C. Young, Jason D. Galpin, Christopher A. Ahern, Bente Vilsen, Pablo Artigas
Summary: The study reveals that a residue Y780 stabilizes the sodium-exclusive ion-binding site of the sodium pump through a hydrogen bond and indirectly controls the interaction of potassium at other ion-binding sites. This finding provides important insights into the mechanism by which the sodium pump distinguishes between sodium and potassium.
JOURNAL OF GENERAL PHYSIOLOGY
(2022)
Article
Immunology
Vivien R. Schack, Morten K. Herlin, Henrik Pedersen, J. Magnus Bernth Jensen, Mia Faerch, Bettina Bundgaard, Rasmus K. Jensen, Uffe B. Jensen, Rikke Christensen, Gregers R. Andersen, Steffen Thiel, Per Hollsberg
Summary: We report a pediatric patient with aHUS carrying a previously unreported homozygous variant in CD46. Functional analyses showed that this variant caused complement dysregulation through multiple mechanisms. These findings highlight the coexistence of multiple mechanisms that may disrupt CD46 function during aHUS development.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Elena Arystarkhova, Mads S. Toustrup-Jensen, Rikke Holm, Jae-Kyun Ko, Kyung Eun Lee, Polina Feschenko, Laurie J. Ozelius, Allison Brashear, Bente Vilsen, Kathleen J. Sweadner
Summary: ATP1A3 encodes the alpha 3 isoform of Na,K-ATPase and is expressed only in neurons. Mutations in this gene result in a variety of phenotypes, with specific syndromes associated with unique substitutions. The pathogenicity of the R756H mutation was tested in mammalian cells and found to have reduced turnover rate, altered ion affinity, and resistance to misfolding.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Ryuta Kanai, Bente Vilsen, Flemming Cornelius, Chikashi Toyoshima
Summary: Na+,K+-ATPase (NKA) plays a crucial role in establishing electrochemical gradients for Na+ and K+ across the cell membrane. This study presents two crystal structures of NKA in different states, providing insight into its reaction cycle and functional roles. The findings demonstrate how NKA converts between different forms and utilizes the lipid bilayer for gating the ion pathway.
Article
Biochemistry & Molecular Biology
Louise S. Mogensen, Stine A. Mikkelsen, Francesco Tadini-Buoninsegni, Rikke Holm, Eli Matsell, Bente Vilsen, Robert S. Molday, Jens Peter Andersen
Summary: P4-ATPases, also known as flippases, play a crucial role in translocating specific lipids across cellular membranes, generating an asymmetric lipid distribution. This study found that in the flippase ATP8A2, the lipid substrate follows a translocation pathway between transmembrane segments M2 and M4 (M2-M4 path). Mutations in this pathway affected the function of the entry site and caused loss of lipid specificity in some mutants, indicating a conformational coupling between the M2-M4 path and the entry site. The residues in the M2-M4 path potentially interact with each other and the lipid substrate, resembling unzipping a zipper of salt bridges/hydrogen bonds.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2024)