Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis
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Author
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
Attention
2299/17729
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 Ca(2+)-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.