Metalloprotease-mediated cleavage of PlexinD1 and its sequestration to actin rods in the motoneuron disease spinal muscular atrophy (SMA).

Autor:	Rademacher S; Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany.; Center for Systems Neuroscience (ZSN), Hannover, Germany., Verheijen BM; Department of Translational Neuroscience & MIND Facility, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.; Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands., Hensel N; Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany., Peters M; Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, and Institute of Genetics, University of Cologne, 50931 Cologne, Germany., Bora G; Department of Medical Biology, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey., Brandes G; Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany., Vieira de Sá R; Department of Translational Neuroscience & MIND Facility, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands., Heidrich N; Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany., Fischer S; Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany., Brinkmann H; Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany., van der Pol WL; Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands., Wirth B; Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, and Institute of Genetics, University of Cologne, 50931 Cologne, Germany., Pasterkamp RJ; Department of Translational Neuroscience & MIND Facility, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands., Claus P; Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany.; Niedersachsen-Research Network on Neuroinfectiology (N-RENNT), Germany.; Center for Systems Neuroscience (ZSN), Hannover, Germany.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2017 Oct 15; Vol. 26 (20), pp. 3946-3959.
DOI:	10.1093/hmg/ddx282
Abstrakt:	Cytoskeletal rearrangement during axon growth is mediated by guidance receptors and their ligands which act either as repellent, attractant or both. Regulation of the actin cytoskeleton is disturbed in Spinal Muscular Atrophy (SMA), a devastating neurodegenerative disease affecting mainly motoneurons, but receptor-ligand interactions leading to the dysregulation causing SMA are poorly understood. In this study, we analysed the role of the guidance receptor PlexinD1 in SMA pathogenesis. We showed that PlexinD1 is cleaved by metalloproteases in SMA and that this cleavage switches its function from an attractant to repellent. Moreover, we found that the PlexinD1 cleavage product binds to actin rods, pathological aggregate-like structures which had so far been described for age-related neurodegenerative diseases. Our data suggest a novel disease mechanism for SMA involving formation of actin rods as a molecular sink for a cleaved PlexinD1 fragment leading to dysregulation of receptor signaling. (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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