Riessland, Markus ORCID: 0000-0003-2592-5045, Kaczmarek, Anna, Schneider, Svenja, Swoboda, Kathryn J., Loehr, Heiko, Bradler, Cathleen, Grysko, Vanessa, Dimitriadi, Maria, Hosseinibarkooie, Seyyedmohsen, Torres-Benito, Laura, Peters, Miriam, Upadhyay, Aaradhita, Biglari, Nasim, Kroeber, Sandra, Hoelker, Irmgard, Garbes, Lutz, Gilissen, Christian ORCID: 0000-0003-1693-9699, Hoischen, Alexander ORCID: 0000-0002-8072-4476, Nuernberg, Gudrun, Nuernberg, Peter, Walter, Michael, Rigo, Frank, Bennett, C. Frank, Kye, Min Jeong ORCID: 0000-0002-1323-7256, Hart, Anne C., Hammerschmidt, Matthias, Kloppenburg, Peter and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2017). Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis. Am. J. Hum. Genet., 100 (2). S. 297 - 316. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

Full text not available from this repository.

Abstract

Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss. However, rarely individuals with homozygous absence of SMN1 and only three to four SMN2 copies are fully asymptomatic, suggesting protection through genetic modifier(s). Previously, we identified plastin 3 (PLS3) overexpression as an SMA protective modifier in humans and showed that SMN deficit impairs endocytosis, which is rescued by elevated PLS3 levels. Here, we identify reduction of the neuronal calcium sensor Neurocalcin delta (NCALD) as a protective SMA modifier in five asymptomatic SMN1-deleted individuals carrying only four SMN2 copies. We demonstrate that NCALD is a Ca2+-dependent negative regulator of endocytosis, as NCALD knockdown improves endocytosis in SMA models and ameliorates pharmacologically induced endocytosis defects in zebrafish. Importantly, NCALD knockdown effectively ameliorates SMA-associated pathological defects across species, including worm, zebrafish, and mouse. In conclusion, our study identifies a previously unknown protective SMA modifier in humans, demonstrates modifier impact in three different SMA animal models, and suggests a potential combinatorial therapeutic strategy to efficiently treat SMA. Since both protective modifiers restore endocytosis, our results confirm that endocytosis is a major cellular mechanism perturbed in SMA and emphasize the power of protective modifiers for understanding disease mechanism and developing therapies.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Riessland, MarkusUNSPECIFIEDorcid.org/0000-0003-2592-5045UNSPECIFIED
Kaczmarek, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, SvenjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Swoboda, Kathryn J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loehr, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bradler, CathleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grysko, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dimitriadi, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hosseinibarkooie, SeyyedmohsenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torres-Benito, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Upadhyay, AaradhitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biglari, NasimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroeber, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelker, IrmgardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garbes, LutzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gilissen, ChristianUNSPECIFIEDorcid.org/0000-0003-1693-9699UNSPECIFIED
Hoischen, AlexanderUNSPECIFIEDorcid.org/0000-0002-8072-4476UNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walter, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rigo, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bennett, C. FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kye, Min JeongUNSPECIFIEDorcid.org/0000-0002-1323-7256UNSPECIFIED
Hart, Anne C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammerschmidt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloppenburg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
URN: urn:nbn:de:hbz:38-239996
DOI: 10.1016/j.ajhg.2017.01.005
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 100
Number: 2
Page Range: S. 297 - 316
Date: 2017
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MOTOR-NEURON GENE; MOUSE MODEL; NERVE-TERMINALS; MESSENGER-RNA; NEUROMUSCULAR-JUNCTIONS; LINKAGE ANALYSIS; SMA PHENOTYPE; PLASTIN 3; SURVIVAL; PROTEINSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23999

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item