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

Riessland, M., Kaczmarek, A., Schneider, S., Swoboda, K.J., Löhr, H., Bradler, C., Grysko, V., Dimitriadi, M., Hosseinibarkooie, S., Torres-Benito, L., Peters, M., Upadhyay, A., Biglari, N., Kröber, S., Hölker, I., Garbes, L., Gilissen, C., Hoischen, A., Nürnberg, G., Nürnberg, P., Walter, M., Rigo, F., Bennett, C.F., Kye, M.J., Hart, A.C., Hammerschmidt, M., Kloppenburg, P., Wirth, B.
American journal of human genetics   100(2): 297-315 (Journal)
Registered Authors
Hammerschmidt, Matthias, Löhr, Heiko
NCALD, PLS3, SMA, SMN1, SMN2, asymptomatic, endocytosis, genetic modifier, incomplete penetrance, neuronal sensor protein, spinal muscular dystrophy
MeSH Terms
  • Animals
  • Caenorhabditis elegans/genetics
  • Cell Line
  • Cloning, Molecular
  • Disease Models, Animal
  • Endocytosis/genetics*
  • Female
  • Gene Expression Regulation
  • Genetic Loci
  • Genome-Wide Association Study
  • Homozygote
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Neurons/pathology
  • Muscular Atrophy, Spinal/genetics*
  • Muscular Atrophy, Spinal/therapy
  • Neurocalcin/genetics
  • Neurocalcin/metabolism*
  • PC12 Cells
  • Pedigree
  • Rats
  • 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
28132687 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes