gms | German Medical Science

60. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie (DGNN)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

26. - 28.08.2015, Berlin

SIGMA1Receptor, of mice and men

Meeting Abstract

  • corresponding author presenting/speaker Hamid Azzedine - Uniklinik-RWTH, Institut for Neuropathologie, Aaachen, Germany
  • Anand Goswami - Uniklinik-RWTH, Institut for Neuropathologie, Aaachen, Germany
  • Nathalie Marrissal-Bernard - Mind Institute, EPFL, Lausanne, Switzerland
  • Estvan Katona - Uniklinik-RWTH, Institut for Neuropathologie, Aaachen, Germany
  • Roman Chrast - Karolinska Institute, Department of Neuroscience, Stockholm, SWEDEN
  • Joachim Weis - Uniklinik-RWTH, Institut for Neuropathologie, Aaachen, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Berlin, 26.-28.08.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. Doc15dgnnOT2

doi: 10.3205/15dgnn23, urn:nbn:de:0183-15dgnn237

Veröffentlicht: 25. August 2015

© 2015 Azzedine et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Introduction: Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits.

Objectives: Better characterise the Sigmar1 KO mice and their motor neurons to understand some of thecellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1.

Materials & methods: In both human and animal tissues we used electron and confocal microscopy and other assays to investigate the biology of SIGMAR1.

Results: Characterization of Sigmar1 KO mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. In primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. The characterization of the human tissue is ongoing and the data could be presented during the meeting.

Conclusion: These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases.