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

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contributor authorRiessland, Markus
contributor authorKaczmarek, Anna
contributor authorSchneider, Svenja
contributor authorSwoboda, Kathryn J
contributor authorLöhr, Heiko
contributor authorBradler, Cathleen
contributor authorGrysko, Vanessa
contributor authorDimitriadi, Maria
contributor authorHosseinibarkooie, Seyyedmohsen
contributor authorTorres-Benito, Laura
contributor authorPeters, Miriam
contributor authorUpadhyay, Aaradhita
contributor authorBiglari, Nasim
contributor authorKröber, Sandra
contributor authorHölker, Irmgard
contributor authorGarbes, Lutz
contributor authorGilissen, Christian
contributor authorHoischen, Alexander
contributor authorNürnberg, Gudrun
contributor authorNürnberg, Peter
contributor authorWalter, Michael
contributor authorRigo, Frank
contributor authorBennett, C Frank
contributor authorKye, Min Jeong
contributor authorHart, Anne C
contributor authorHammerschmidt, Matthias
contributor authorKloppenburg, Peter
contributor authorWirth, Brunhilde
date accessioned2017-03-17T17:10:20Z
date available2017-03-17T17:10:20Z
date issued2017-02-02
identifier citationRiessland , 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 2017 , ' Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis ' American Journal of Human Genetics , vol 100 , no. 2 , pp. 297-315 . DOI: 10.1016/j.ajhg.2017.01.005en
identifier issn0002-9297
identifier otherPURE: 11117363
identifier otherPURE UUID: ecd60062-7052-45c5-bd8f-eadb5b1269b8
identifier otherPubMed: 28132687
identifier otherScopus: 85010918273
identifier uri
descriptionThis 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: © 2017 American Society of Human Genetics.en
description abstractHomozygous 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.en
format extent19en
language isoeng
relation ispartofAmerican Journal of Human Geneticsen
subjectspinal muscular dystrophyen
subjectgenetic modifieren
subjectneural sensor proteinen
subjectincomplete penetranceen
titleNeurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosisen
contributor institutionSchool of Life and Medical Sciencesen
contributor institutionDepartment of Biological and Environmental Sciencesen
contributor institutionGeography, Environment and Agricultureen
contributor institutionBiosciences Research Groupen
identifier doi
description versionauthorsversionen
description statusPeer revieweden
date embargoedUntil26-07-20

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