Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis

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 expressi...

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Bibliographic Details
Published in:American journal of human genetics 2017-02, Vol.100 (2), p.297-315
Main Authors: Riessland, Markus, Kaczmarek, Anna, Schneider, Svenja, Swoboda, Kathryn J., Löhr, Heiko, Bradler, Cathleen, Grysko, Vanessa, Dimitriadi, Maria, Hosseinibarkooie, Seyyedmohsen, Torres-Benito, Laura, Peters, Miriam, Upadhyay, Aaradhita, Biglari, Nasim, Kröber, Sandra, Hölker, Irmgard, Garbes, Lutz, Gilissen, Christian, Hoischen, Alexander, Nürnberg, Gudrun, Nürnberg, Peter, Walter, Michael, Rigo, Frank, Bennett, C. Frank, Kye, Min Jeong, Hart, Anne C., Hammerschmidt, Matthias, Kloppenburg, Peter, Wirth, Brunhilde
Format: Article
Language:English
Subjects:
Animals
asymptomatic
Caenorhabditis elegans - genetics
Cell Line
Cloning, Molecular
Disease Models, Animal
Endocytosis
Endocytosis - genetics
Female
Gene Expression Regulation
Genetic disorders
Genetic Loci
genetic modifier
Genome-Wide Association Study
Genotype & phenotype
Homozygote
Humans
incomplete penetrance
Male
Mice
Mice, Inbred C57BL
Motor Neurons - pathology
Muscular Atrophy, Spinal - genetics
Muscular Atrophy, Spinal - therapy
Musculoskeletal diseases
NCALD
Neurocalcin - genetics
Neurocalcin - metabolism
neuronal sensor protein
Neurons
PC12 Cells
Pedigree
PLS3
Protein expression
Rats
SMA
SMN1
SMN2
spinal muscular dystrophy
Survival of Motor Neuron 1 Protein - genetics
Survival of Motor Neuron 1 Protein - metabolism
Survival of Motor Neuron 2 Protein - genetics
Survival of Motor Neuron 2 Protein - metabolism
Transcriptome
Zebrafish - genetics
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Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2017.01.005