Hosseinibarkooie, Seyyedmohsen, Peters, Miriam, Torres-Benito, Laura, Rastetter, Raphael H., Hupperich, Kristina, Hoffmann, Andrea, Mendoza-Ferreira, Natalia, Kaczmarek, Anna, Janzen, Eva, Milbradt, Janine, Lamkemeyer, Tobias, Rigo, Frank, Bennett, C. Frank, Guschlbauer, Christoph, Bueschges, Ansgar, Hammerschmidt, Matthias, Riessland, Markus ORCID: 0000-0003-2592-5045, Kye, Min Jeong ORCID: 0000-0002-1323-7256, Clemen, Christoph S. and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2016). The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype. Am. J. Hum. Genet., 99 (3). S. 647 - 666. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

Homozygous loss of SMN1 causes spinal muscular atrophy (SMA), the most common and devastating childhood genetic motor-neuron disease. The copy gene SMN2 produces only similar to 10% functional SMN protein, insufficient to counteract development of SMA. In contrast, the human genetic modifier plastin 3 (PLS3), an actin-binding and-bundling protein, fully protects against SMA in SMN/-deleted individuals carrying 3-4 SMN2 copies. Here, we demonstrate that the combinatorial effect of suboptimal SMN antisense oligonucleotide treatment and PLS3 overexpression a situation resembling the human condition in asymptomatic SMN1-deleted individuals rescues survival (from 14 to >250 days) and motoric abilities in a severe SMA mouse model. Because PLS3 knockout in yeast impairs endocytosis, we hypothesized that disturbed endocytosis might be a key cellular mechanism underlying impaired neurotransmission and neuromuscular junction maintenance in SMA. Indeed, SMN deficit dramatically reduced endocytosis, which was restored to normal levels by PLS3 overexpression. Upon low-frequency electro-stimulation, endocytotic FM1-43 (SynaptoGreen) uptake in the presynaptic terminal of neuromuscular junctions was restored to control levels in SMA-PLS3 mice. Moreover, proteomics and biochemical analysis revealed CORO1C, another F-actin binding protein, whose direct binding to PLS3 is dependent on calcium. Similar to PLS3 overexpression, CORO1C overexpression restored fluid-phase endocytosis in SMN-knockdown cells by elevating F-actin amounts and rescued the axonal truncation and branching phenotype in Smn-depleted zebrafish. Our findings emphasize the power of genetic modifiers to unravel the cellular pathomechanisms underlying SMA and the power of combinatorial therapy based on splice correction of SMN2 and endocytosis improvement to efficiently treat SMA.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hosseinibarkooie, SeyyedmohsenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torres-Benito, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rastetter, Raphael H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hupperich, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mendoza-Ferreira, NataliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaczmarek, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janzen, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milbradt, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lamkemeyer, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rigo, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bennett, C. FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guschlbauer, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bueschges, AnsgarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammerschmidt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riessland, MarkusUNSPECIFIEDorcid.org/0000-0003-2592-5045UNSPECIFIED
Kye, Min JeongUNSPECIFIEDorcid.org/0000-0002-1323-7256UNSPECIFIED
Clemen, Christoph S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
URN: urn:nbn:de:hbz:38-265309
DOI: 10.1016/j.ajhg.2016.07.014
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 99
Number: 3
Page Range: S. 647 - 666
Date: 2016
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SURVIVAL-MOTOR-NEURON; MORPHOLINO ANTISENSE OLIGOMER; DISEASE GENE-PRODUCT; MOUSE MODEL; NEUROMUSCULAR-JUNCTION; MESSENGER-RNA; STEP PURIFICATION; NERVE-TERMINALS; ACTIN DYNAMICS; CELL-DEATHMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26530

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