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Am J Hum Genet. 2017 Feb 2;100(2):297-315. doi: 10.1016/j.ajhg.2017.01.005. Epub 2017 Jan 26.

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

Author information

1
Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
2
MassGeneral Hospital for Children, Boston, MA 02115, USA.
3
Institute for Zoology - Developmental Biology, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
4
Institute for Zoology - Neurophysiology University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
5
Department of Neuroscience, Brown University, Providence, RI 02912, USA.
6
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
7
Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Genomics Cologne, University of Cologne, 50931 Cologne, Germany.
8
Institute of Medical Genetics, University of Tübingen, 72076 Tübingen, Germany.
9
IONIS Pharmaceuticals, Carlsbad, CA 92008, USA.
10
Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
11
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Zoology - Developmental Biology, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
12
Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany. Electronic address: brunhilde.wirth@uk-koeln.de.

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 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.

KEYWORDS:

NCALD; PLS3; SMA; SMN1; SMN2; asymptomatic; endocytosis; genetic modifier; incomplete penetrance; neuronal sensor protein; spinal muscular dystrophy

PMID:
28132687
PMCID:
PMC5294679
DOI:
10.1016/j.ajhg.2017.01.005
[Indexed for MEDLINE]
Free PMC Article

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