About us

The Orth Group studies Huntington’s Disease (HD), a hereditary movement disorder with dementia and behavioural difficulties. Twenty years after the discovery of the causal CAG repeat expansion mutation in the HTT gene, Huntington’s disease remains an incurable, devastating disorder. However, using disease models, and studies in human patients, great progress has been made in understanding the pathophysiology of HD. Research has led to the development of the first gene therapy approaches with promising results in HD model systems.

We are interested in research in three main areas:

he evidence for macro- and micro-structural abnormalities in in brains of HD patients does not fully explain the considerable heterogeneity of the clinical features or the rates of disease progression. This suggests that structural abnormalities do not directly predict brain function or behaviour. To better understand the relationship between brain structure, brain function and behavior we examine the neural circuits underlying sensory-motor integration. Sensory-motor integration is of fundamental importance for everyday life such as the use of one’s hands. To do this we use structural and functional neuroimaging techniques, and electrophysiological techniques, like transcranial magnetic stimulation or electroencephalography.

Collaborators

Professor Georg Grön, Department of Psychiatry, Ulm University

Professor Thomas Kammer, Department of Psychiatry, Ulm University

Dr Hans-Peter Müller and Professor Jan Kassubek, Department of Neurology, Ulm University

Professor Christian Wolf, Department of Psychiatry, Heidelberg University

Professor John C. Rothwell, Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, UK

Professor Sarah Tabrizi, Department of Neurodegenerative Disease, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

HD predominantly, but not exclusively, affects the brain. This is important because evidence for HD pathology beyond the brain means that peripheral tissues may serve as a source for biomarkers. Similar to the brain several peripheral tissues may have compromised mitochondrial biology.  The mitochondrial signature in the most easily accessible peripheral tissues thus has biomarker potential for HD including the prodromal phase where HD expansion mutation carriers are well. We examine many aspects of the mitochondrial biology including respiratory chain activity, ATP generation, biogenesis, mitochondrial dynamics and mitophagy.

Collaborators

Dr Jan-Willem Taanman, Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK

Professor Sarah Tabrizi, Department of Neurodegenerative Disease, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

Dr Maria Demestre, Institute of Anatomy and Cell Biology, Ulm University

The HTT gene codes for the fairly large HTT protein. In addition to this full-length protein several smaller fragments of the HTT protein exist. Some of these fragments may result from proteolytic cleavage of the full-length protein. However, the production of the most toxic fragment, derived from exon 1 of HTT, is generated through a different mechanism. A block in the splicing reaction of exon 1 to exon 2 of the HTT mRNA leads to the generation of a transcript that only encodes for exon 1 HTT. We try to understand the mechanisms that contribute to the generation of this transcript and its implications on RNA homeostasis in HD.

Collaborators

Prof. Gillian Bates, University College London, United Kingdom

Prof. Sarah Tabrizi, University College London, United Kingdom

Prof. Beverly Davidson, The Children's Hospital of Philadelphia, United States of America.

Prof. Andrew Lieberman, University of Michigan, United States of America.

Prof. Xiao-Jiang Li, Emory University, United States of America.

Dr. Yvon Trottier, University of Strasbourg, France.

 
Team
Profilbild von Prof. Dr. Michael Orth

Prof. Dr. Michael Orth

Andreas Neueder, PhD

Department of Neurology
Ulm University
Helmholtzstraße 8/1
89081 Ulm
Germany

email: andreas.neueder@uni-ulm.de
web: https://neuederlab.bitrix24.site/

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Nathalie Birth, technician

Department of Neurology
Ulm University
Helmholtzstraße 8/1
89081 Ulm
Germany

phone lab: +49 (0)731-500 63115
email: nathalie.birth@uni-ulm.de

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Alumni

Kerstin Kojer, PhD

Maximilian Fischer, MD

Medea Tabitha Müller, BSc

Tanja Hering, PhD

Isabella Mayer, Dr hum-biol

Eva-Maria Baldas, MD

Gesa Gruppe, MD

 

 

Publications
  • Chao MJ, Kim KH, Shin JW, Lucente D, Wheeler VC, Li H, Roach JC, Hood L, Wexler NS, Jardim LB, Holmans P, Jones L, Orth M, Kwak S, MacDonald ME, Gusella JF, Lee JM. Population-specific genetic modification of Huntington's disease in Venezuela. PLoS Genet. 2018 May 11;14(5):e1007274. doi:10.1371/journal.pgen.1007274.
  • Gregory S, Crawford H, Seunarine K, Leavitt B, Durr A, Roos RAC, Scahill RI, Tabrizi SJ, Rees G, Langbehn D, Orth M. Natural biological variation of white matter microstructure is accentuated in Huntington's disease. Hum Brain Mapp. 2018 Apr 22. doi: 10.1002
  • Casula EP, Mayer IMS, Desikan M, Tabrizi SJ, Rothwell JC, Orth M. Motor cortex synchronization influences the rhythm of motor performance in premanifest huntington's disease. Mov Disord. 2018 Mar;33(3):440-448. doi: 10.1002
  • Lee JM, Chao MJ, Harold D, Abu Elneel K, Gillis T, Holmans P, Jones L, Orth M, Myers RH, Kwak S, Wheeler VC, MacDonald ME, Gusella JF. A modifier of Huntington's disease onset at the MLH1 locus. Hum Mol Genet. 2017 Oct 1;26(19):3859-3867. doi: 10.1093
  • Brown KE, Lohse KR, Mayer IMS, Strigaro G, Desikan M, Casula EP, Meunier S, Popa T, Lamy JC, Odish O, Leavitt BR, Durr A, Roos RAC, Tabrizi SJ, Rothwell JC, Boyd LA, Orth M. The reliability of commonly used electrophysiology measures. Brain Stimul. 2017 Nov - Dec;10(6):1102-1111. doi: 10.1016
  • Gorges M, Müller HP, Mayer IM, Grupe GS, Kammer T, Grön G, Kassubek J, Landwehrmeyer GB, Wolf RC, Orth M. Intact sensory-motor network structure and function in far from onset premanifest Huntington's disease. Sci Rep. 2017 Mar 7;7:43841. doi: 10.1038
  • Hering T, Kojer K, Birth N, Hallitsch J, Taanman JW, Orth M. Mitochondrial cristae remodelling is associated with disrupted OPA1 oligomerisation in the Huntington's disease R6/2 fragment model. Exp Neurol. 2017 Feb;288:167-175. doi: 10.1016
  • Braisch U, Hay B, Muche R, Rothenbacher D, Landwehrmeyer GB, Long JD, Orth M; REGISTRY Investigators of the European Huntington's Disease Network and COHORT Investigators of the Huntington Study Group. Identification of extreme motor phenotypes in Huntington's disease. Am J Med Genet B Neuropsychiatr Genet. 2017 Apr;174(3):283-294. doi: 10.1002
  • Orth M, Gregory S, Scahill RI, Mayer IS, Minkova L, Klöppel S, Seunarine KK, Boyd L, Borowsky B, Reilmann R, Bernhard Landwehrmeyer G, Leavitt BR, Roos RA, Durr A, Rees G, Rothwell JC, Langbehn D, Tabrizi SJ; TRACK-On Investigators. Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease. Hum Brain Mapp. 2016 Dec;37(12):4615-4628. doi: 10.1002
  • Keum JW, Shin A, Gillis T, Mysore JS, Abu Elneel K, Lucente D, Hadzi T, Holmans P, Jones L, Orth M, Kwak S, MacDonald ME, Gusella JF, Lee JM. The HTT CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease. Am J Hum Genet. 2016 Feb 4;98(2):287-98. doi: 10.1016
  • Demestre M, Orth M, Föhr KJ, Achberger K, Ludolph AC, Liebau S, Boeckers TM. Formation and characterisation of neuromuscular junctions between hiPSC derived motoneurons and myotubes. Stem Cell Res. 2015 Sep;15(2):328-36. doi: 10.1016
  • Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016
  • Hering T, Birth N, Taanman JW, Orth M. Selective striatal mtDNA depletion in end-stage Huntington's disease R6/2 mice. Exp Neurol. 2015 Apr;266:22-9. doi: 10.1016
  • Progressive hepatic mitochondrial dysfunction in premanifest Huntington's disease. Hoffmann R, Stüwe SH, Goetze O, Banasch M, Klotz P, Lukas C, Tegenthoff M, Beste C, Orth M, Saft C Mov Disord. 2014 May;29(6):831-4. doi: 10.1002/mds.25862.
  • Visual system integrity and cognition in early Huntington's disease.  Wolf RC, Sambataro F, Vasic N, Baldas EM, Ratheiser I, Bernhard Landwehrmeyer G, Depping MS, Thomann PA, Sprengelmeyer R, Süssmuth SD, Orth M. Eur J Neurosci. 2014 Apr 3. doi: 10.1111/ejn.12575.
  • β-Defensin Genomic Copy Number Does Not Influence the Age of Onset in Huntington's Disease. Vittori A, Orth M, Roos RA, Outeiro TF, Giorgini F, Hollox EJ; REGISTRY investigators of the European Huntington’s Disease Network. J Huntingtons Dis. 2013 Mar 27;2(1):107-124.
  • Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease. Vittori A, Breda C, Repici M, Orth M, Roos RA, Outeiro TF, Giorgini F, Hollox EJ; REGISTRY investigators of the European Huntington's Disease Network. Hum Mol Genet. 2014 Jun 15;23(12):3129-37. doi:10.1093/hmg/ddu022.
  • The neuroanatomy of subthreshold depressive symptoms in Huntington's disease: a combined diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) study. Sprengelmeyer R*, Orth M*, Müller HP, Wolf RC, Grön G, Depping MS, Kassubek J, Justo D, Rees EM, Haider S, Cole JH, Hobbs NZ, Roos RA, Dürr A, Tabrizi SJ, Süssmuth SD, Landwehrmeyer GB. Psychol Med. 2013 Oct 7:1-12. *equal first authors
  • Longitudinal task-negative network analyses in preclinical Huntington's disease. Wolf RC, Sambataro F, Vasic N, Wolf ND, Thomann PA, Landwehrmeyer GB, Orth M. Eur Arch Psychiatry Clin Neurosci. 2013 Sep 27.
  • Hepatic mitochondrial dysfunction in manifest and premanifest Huntington disease. Stüwe SH, Goetze O, Lukas C, Klotz P, Hoffmann R, Banasch M, Orth M, Schmidt WE, Gold R, Saft C. Neurology. 2013 Feb 19;80(8):743-6.
  • Brain Structure in Preclinical Huntington's Disease: A Multi-Method Approach. Wolf RC, Thomann PA, Thomann AK, Vasic N, Wolf ND, Landwehrmeyer GB, Orth M. Neurodegener Dis. 2013;12(1):13-22.
  • Transcranial magnetic stimulation studies of sensorimotor networks in Tourette syndrome. Orth M, Münchau A. Behavioral Neurology, 2013;27(1):57-64.
  • Default-mode network changes in preclinical Huntington's disease. Wolf RC, Sambataro F, Vasic N, Wolf ND, Thomann PA, Saft C, Landwehrmeyer GB, Orth M. Exp Neurol. 2012 Sep;237(1):191-8.
  • Brain activation and functional connectivity in premanifest Huntington's disease during states of intrinsic and phasic alertness. Wolf RC, Grön G, Sambataro F, Vasic N, Wolf ND, Thomann PA, Saft C, Landwehrmeyer GB, Orth M. Hum Brain Mapp, 2012 Sep;33(9):2161-73.
  • Rate of change in early Huntington's disease: a clinicometric analysis. Meyer C, Landwehrmeyer B, Schwenke C, Doble A, Orth M, Ludolph AC; EHDI Study Group. Mov Disord. 2012 Jan;27(1):118-24.
  • Short-latency sensory afferent inhibition: conditioning stimulus intensity, recording site, and effects of 1 Hz repetitive TMS. Fischer M, Orth M. Brain Stimulation, 2011 Oct;4(4):202-9.
  • Magnetic resonance perfusion imaging of resting-state cerebral blood flow in preclinical Huntington’s disease.  Wolf RC, Grön G, Sambataro F, Vasic N, Wolf ND, Thomann PA, Saft C, Landwehrmeyer GB, Orth M. Journal of Cerebral Blood Flow and Metabolism, 2011 Sep;31(9):1908-18.
  • Longitudinal functional magnetic resonance imaging of cognition in preclinical Huntington's disease. Wolf RC, Sambataro F, Vasic N, Wolf ND, Thomann PA, Landwehrmeyer GB, Orth M. Exp Neurol. 2011 Oct;231(2):214-22.
  • Abnormal motor cortex plasticity in premanifest and very early manifest Huntington disease. Orth M, Schippling S, Schneider SA, Bhatia KP, Talelli P, Tabrizi SJ, Rothwell JC. J Neurol Neurosurg Psychiatry. 2010 Mar;81(3):267-70.
  • Observing Huntington’s disease: the European Huntington’s Disease Network’s REGISTRY. Orth M for the European Huntington’s Disease Network. J Neurol Neurosurg Psychiatry, 2010 Nov 19. [Epub ahead of print].
  • Abnormal motor cortex excitability in preclinical and very early Huntington's disease. Schippling S, Schneider SA, Bhatia KP, Münchau A, Rothwell JC, Tabrizi SJ, Orth M. Biol Psychiatry. 2009 Jun 1;65(11):959-65.
  • Cortico-spinal system excitability at rest is associated with tic severity in Tourette syndrome. Orth M, Münchau AM, Rothwell JC. Biol Psychiatry 2008;64(3):248-51.
  • Motor inhibition in patients with Gilles de la Tourette syndrome: functional activation patterns as revealed by EEG-EEG coherence. Serrien DJ, Orth M, Evans AH, Lees AJ, Brown P. Brain, 2005; 128:116-125.
  • Excitability of motor cortex inhibitory circuits in Tourette syndrome before and after single dose nicotine. Orth M, Amann B, Robertson MM, Rothwell JC. Brain 2005; 128:1292-1300.
  • Grip force behaviour in Gilles de la Tourette syndrome. Nowak DA, Rothwell JC, Topka H, Robertson MM, Orth M. Mov Disord, 2005;20: 217-223.
  • Caffeine has no effect on measures of cortical excitability. Orth M, Amann B, Ratnaraj N, Patsalos PN, Rothwell JC. Clin Neurophysiol, 2005; Feb;116(2):308-14.
  • ALS IgG induced selective motor neurone apoptosis in rat mixed primary spinal cord cultures. Demestre M, Pullen A, Orrell RW, Orth M. J Neurochem, 2005; Jul;94(1):268-75.
  • G209A mutant alpha-synuclein expression specifically enhances dopamine induced oxidative stress. Orth M, Tabrizi SJ, Tomlinson C, Messmer K, Korlipara LVP, Schapira AHV, Cooper JM. Neurochem Int, 2004 Oct;45(5):669-76.
  • The cortical silent period- inherent variability and influence of TMS pulse waveform. Orth M, Rothwell JC. Clin Neurophysiol. 2004 May;115(5):1076-82.
  • Inclusion formation in Huntington’s disease R6/2 mouse muscle cultures. Orth M, Cooper JM, Bates GP, Schapira AHV. J Neurochem. 2003 Oct;87(1):1-6.
  • Alpha-synuclein expression in HEK293 cells enhances the mitochondrial sensitivity to rotenone. Orth M, Tabrizi SJ, Cooper JM, Schapira AHV. Neurosci Lett. 2003 Nov 6;351(1):29-32.
  • The variability of intracortical inhibition and facilitation. Orth M, Snijders AH, Rothwell JC. Clin Neurophysiol. 2003;114:2362-9.
  • Effect of acid maltase deficiency on the endosomal/lysosomal system and glucose transporter 4. Orth M, Mundegar RR. Neuromuscul Disord 2003; 13:49-54.
  • Replication of mitochondrial DNA occurs throughout the mitochondria of cultured human cells. Magnussen C, Orth M, Lestienne P, Taanman JW. Exp Cell Res. 2003 Sep 10;289(1):133-42.
  • Expression of mutant a-synuclein causes increased susceptibility to dopamine toxicity. Tabrizi SJ*, Orth M*, Wilkinson JM, Taanman JW, Warner TT, Cooper JM, Schapira AHV. Hum Mol Gen 2000; 9:2683-9. *equal first authors.
  • Sporadic inclusion body myositis is not linked to Methionine homozygosity of codon 129 of the prion protein.  Orth M, Tabrizi SJ, Schapira AHV. Neurology. 2000;55(8):1235.
 
Funding

EU FP7

CHDI Foundation, Inc.

Contact

Telefon 0731-500 63023

Telefax 0731-500 63082

Michael Orth, MD, PhD
Professor of Neurology
EHDN Central Coordination
Science Management
Department of Neurology
Ulm University
Oberer Eselsberg 45/1
89081 Ulm
Germany