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

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• 作者：Markus Riessland¹ ; ² ; ³ ; ¹³ ; ¹⁴ ; Anna Kaczmarek¹ ; ² ; ³ ; ¹³ ; Svenja Schneider¹ ; ² ; ³ ; ¹³ ; Kathryn J. Swoboda⁴ ; Heiko Lö ; hr⁵ ; ⁷ ; Cathleen Bradler⁶ ; ⁷ ; Vanessa Grysko¹ ; ² ; ³ ; Maria Dimitriadi⁸ ; ¹⁵ ; Seyyedmohsen Hosseinibarkooie¹ ; ² ; ³ ; Laura Torres-Benito¹ ; ² ; ³ ; Miriam Peters¹ ; ² ; ³ ; Aaradhita Upadhyay¹ ; ² ; ³ ; Nasim Biglari¹ ; ² ; ³ ; Sandra Krö ; ber¹ ; ² ; ³ ; Irmgard Hö ; lker¹ ; ² ; ³ ; Lutz Garbes¹ ; ² ; ³ ; Christian Gilissen⁹ ; Alexander Hoischen⁹ ; Gudrun Nü ; rnberg⁷ ; ¹⁰ ; Peter Nü ; rnberg⁷ ; ¹⁰ ; Michael Walter¹¹ ; Frank Rigo¹² ; C. Frank Bennett¹² ; Min Jeong Kye¹ ; ² ; Anne C. Hart⁸ ; Matthias Hammerschmidt² ; ⁵ ; ⁷ ; Peter Kloppenburg⁶ ; ⁷ ; Brunhilde Wirth¹ ; ² ; ³ ; ^{brunhilde.wirth@uk-koeln.de}
• 关键词：spinal muscular dystrophy ; SMA ; genetic modifier ; NCALD ; endocytosis ; asymptomatic ; SMN2 ; SMN1 ; neuronal sensor protein ; PLS3 ; incomplete penetrance
• 刊名：The American Journal of Human Genetics
• 出版年：2017
• 出版时间：2 February 2017
• 年：2017
• 卷：100
• 期：2
• 页码：297-315
• 全文大小：3262 K
• 卷排序：100

文摘

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.