TY - JOUR
T1 - Metalloprotease-mediated cleavage of PlexinD1 and its sequestration to actin rods in the motoneuron disease spinal muscular atrophy (SMA)
AU - Rademacher, Sebastian
AU - Verheijen, Bert M.
AU - Hensel, Niko
AU - Peters, Miriam
AU - Bora, Gamze
AU - Brandes, Gudrun
AU - de Sá, Renata Vieira
AU - Heidrich, Natascha
AU - Fischer, Silke
AU - Brinkmann, Hella
AU - van der Pol, W. Ludo
AU - Wirth, Brunhilde
AU - Pasterkamp, R. Jeroen
AU - Claus, Peter
N1 - Funding Information:
We thank Dr. Andreas Ratzka for providing the Plxnd1 primers and Dr. F. Mann, Aix Marseille Univ, CNRS, IBDM, Marseille, France, for providing plasmids. Furthermore, we thank Sandra Kling, Oliver Harschnitz, Liset Rietman and Lill Eva Johansen for help with generating iPSC lines and motoneuron differentiation. Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony, the Initiative SMA, and the Deutsche Muskelstiftung/Philipp & Freunde-SMA Deutschland e.V. to P.C, by a grant from SMA Europe (to N.Hen.), by a grant from Stichting Spieren voor Spieren to W.L.v.d.P., the ALS Stichting (TOTALS to R.J.P) as well as the Deutsche Forschungsgemeinschaft Wi945/14-3, RTG1970 and CMMC C11 to B.W.
Publisher Copyright:
© The Author 2017. Published by Oxford University Press. All rights reserved.
PY - 2017/10/15
Y1 - 2017/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85031734977&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddx282
DO - 10.1093/hmg/ddx282
M3 - Article
C2 - 29016853
AN - SCOPUS:85031734977
SN - 0964-6906
VL - 26
SP - 3946
EP - 3959
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 20
ER -