PUBLICATION

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

Authors

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.

ID

ZDB-PUB-170131-8

Date

2017

Source

American journal of human genetics 100(2): 297-315 (Journal)

Registered Authors

Hammerschmidt, Matthias, Löhr, Heiko

Keywords

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

PubMed

28132687 Full text @ Am. J. Hum. Genet.

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.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Mutations / Transgenics

Human Disease / Model

Sequence Targeting Reagents

Fish

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Riessland et al., 2017 ZDB-PUB-170131-8 PMID:28132687

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

Riessland et al., 2017

ZDB-PUB-170131-8
PMID:28132687