Rademacher, Sebastian ORCID: 0000-0002-1592-9838, Verheijen, Bert M., Hensel, Niko, Peters, Miriam, Bora, Gamze, Brandes, Gudrun, de Sa, Renata Vieira, Heidrich, Natascha, Fischer, Silke, Brinkmann, Hella, van der Pol, W. Ludo, Wirth, Brunhilde ORCID: 0000-0003-4051-5191, Pasterkamp, R. Jeroen and Claus, Peter ORCID: 0000-0003-3824-9445 (2017). Metalloprotease-mediated cleavage of PlexinD1 and its sequestration to actin rods in the motoneuron disease spinal muscular atrophy (SMA). Hum. Mol. Genet., 26 (20). S. 3946 - 3960. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rademacher, SebastianUNSPECIFIEDorcid.org/0000-0002-1592-9838UNSPECIFIED
Verheijen, Bert M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hensel, NikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bora, GamzeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandes, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Sa, Renata VieiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heidrich, NataschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, SilkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkmann, HellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Pol, W. LudoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
Pasterkamp, R. JeroenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claus, PeterUNSPECIFIEDorcid.org/0000-0003-3824-9445UNSPECIFIED
URN: urn:nbn:de:hbz:38-214211
DOI: 10.1093/hmg/ddx282
Journal or Publication Title: Hum. Mol. Genet.
Volume: 26
Number: 20
Page Range: S. 3946 - 3960
Date: 2017
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MOTOR-NEURONS; MOUSE MODEL; MATRIX METALLOPROTEINASES; IMPAIRED ENDOCYTOSIS; NEURAL DEVELOPMENT; DETERMINING GENE; SEMAPHORIN 3E; AXON GROWTH; STEM-CELLS; EXPRESSIONMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21421

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