University of Hertfordshire

Documents

  • Markus Riessland
  • Anna Kaczmarek
  • Svenja Schneider
  • Kathryn J Swoboda
  • Heiko Löhr
  • Cathleen Bradler
  • Vanessa Grysko
  • Seyyedmohsen Hosseinibarkooie
  • Laura Torres-Benito
  • Miriam Peters
  • Aaradhita Upadhyay
  • Nasim Biglari
  • Sandra Kröber
  • Irmgard Hölker
  • Lutz Garbes
  • Christian Gilissen
  • Alexander Hoischen
  • Gudrun Nürnberg
  • Peter Nürnberg
  • Michael Walter
  • Frank Rigo
  • C Frank Bennett
  • Min Jeong Kye
  • Anne C Hart
  • Matthias Hammerschmidt
  • Peter Kloppenburg
  • Brunhilde Wirth
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Original languageEnglish
Number of pages19
Pages (from-to)297-315
JournalAmerican Journal of Human Genetics
Journal publication date2 Feb 2017
Volume100
Issue2
Early online date26 Jan 2017
DOIs
Publication statusPublished - 2 Feb 2017

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.

Notes

This document is the Accepted Manuscript version of the following article: Riessland et al., 'Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis', The American Journal of Human Genetics, Vol. 100 (2): 297-315, first published online 26 January 2017. The final, published version is available online at doi: http://dx.doi.org/10.1016/j.ajhg.2017.01.005 © 2017 American Society of Human Genetics.

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