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

Markus Riessland, Anna Kaczmarek, Svenja Schneider, Kathryn J Swoboda, Heiko Löhr, Cathleen Bradler, Vanessa Grysko, Maria Dimitriadi, Seyyedmohsen Hosseinibarkooie, Laura Torres-Benito, Miriam Peters, Aaradhita Upadhyay, Nasim Biglari, Sandra Kröber, Irmgard Hölker, Lutz Garbes, Christian Gilissen, Alexander Hoischen, Gudrun Nürnberg, Peter NürnbergMichael Walter, Frank Rigo, C Frank Bennett, Min Jeong Kye, Anne C Hart, Matthias Hammerschmidt, Peter Kloppenburg, Brunhilde Wirth

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)297-315
Number of pages19
JournalAmerican Journal of Human Genetics
Volume100
Issue number2
Early online date26 Jan 2017
DOIs
Publication statusPublished - 2 Feb 2017

Keywords

  • spinal muscular dystrophy
  • SMA
  • genetic modifier
  • NCALD
  • ENDOCYTOSIS
  • asymptomatic
  • SMN2
  • SMN1
  • neural sensor protein
  • PLS3
  • incomplete penetrance

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