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| Status |
Public on Jan 01, 2015 |
| Title |
Suppression of NCALD protects against spinal muscular atrophy by restoring impaired endocytosis |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Spinal muscular atrophy (SMA) is a common genetic motor neuron (MN) disease caused by low levels of the ubiquitously expressed housekeeping survival motor neuron (SMN) protein, whereas concomitant overexpression of plastin 3 (PLS3) protects from SMA. Here we identify neurocalcin delta (NCALD), a neuronal calcium sensor, as a second fully protective SMA modifier, which counteracts SMA pathology when downregulated. We show reduced Ca2+ influx and impaired endocytosis in SMA, which are crucial processes in synaptic vesicle recycling and neurotransmission. Remarkably, both reduced NCALD or increased PLS3 restore endocytosis in cell culture and MN function across species in zebrafish, worm and mouse SMA models, whereas Ca2+ influx remains disturbed. Furthermore, NCALD physically binds clathrin in a Ca2+-dependent manner. We propose that NCALD acts as a Ca2+-regulated inhibitor of endocytosis, and that endocytosis is critically affected in SMA. This finding opens new therapeutic avenues for SMA.
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| Overall design |
Multifactorial design comparing affected patients and unaffected disease carriers against severly affected control group to identify disease modifying transcripts
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| Contributor(s) |
Riessland M, Swoboda KJ, Löhr H, Bradler C, Dimitriadi M, Kaczmarek A, Schneider S, Mohsen S, Barkooie H, Peters M, Bigliari N, Grysko V, Kröber S, Hölker I, Garbes L, Gilissen C, Hoischen A, Nürnberg G, Nürnberg P, Walter M, Kye MJ, Hart A, Hammerschmidt M, Kloppenburg P, Wirth B |
| Citation(s) |
28132687 |
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| Submission date |
Jun 09, 2014 |
| Last update date |
Jul 10, 2019 |
| Contact name |
Michael H. Walter |
| E-mail(s) |
michael.walter@agilent.com
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| Organization name |
University of Tuebingen
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| Department |
Department of Medical Genetics
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| Lab |
The Microarray Facility Tübingen
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| Street address |
Calwer Str. 7
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| City |
Tuebingen |
| ZIP/Postal code |
72076 |
| Country |
Germany |
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| Platforms (1) |
| GPL6947 |
Illumina HumanHT-12 V3.0 expression beadchip |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA251983 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE58316_RAW.tar |
6.2 Mb |
(http)(custom) |
TAR |
| GSE58316_non-normalized.txt.gz |
3.9 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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