Universität zu Köln

Heesen, Ludwig, Peitz, Michael, Torres-Benito, Laura, Hoelker, Irmgard, Hupperich, Kristina, Dobrindt, Kristina, Jungverdorben, Johannes, Ritzenhofen, Swetlana, Weykopf, Beatrice, Eckert, Daniela, Hosseini-Barkooie, Seyyed Mohsen, Storbeck, Markus, Fusaki, Noemi, Lonigro, Renata, Heller, Raoul, Kye, Min Jeong ORCID: 0000-0002-1323-7256, Bruestle, Oliver and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2016). Plastin 3 is upregulated in iPSC-derived motoneurons from asymptomatic SMN1-deleted individuals. Cell. Mol. Life Sci., 73 (10). S. 2089 - 2105. BASEL: SPRINGER BASEL AG. ISSN 1420-9071

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Abstract

Spinal muscular atrophy (SMA) is a devastating motoneuron (MN) disorder caused by homozygous loss of SMN1. Rarely, SMN1-deleted individuals are fully asymptomatic despite carrying identical SMN2 copies as their SMA III-affected siblings suggesting protection by genetic modifiers other than SMN2. High plastin 3 (PLS3) expression has previously been found in lymphoblastoid cells but not in fibroblasts of asymptomatic compared to symptomatic siblings. To find out whether PLS3 is also upregulated in MNs of asymptomatic individuals and thus a convincing SMA protective modifier, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of three asymptomatic and three SMA III-affected siblings from two families and compared these to iPSCs from a SMA I patient and control individuals. MNs were differentiated from iPSC-derived small molecule neural precursor cells (smNPCs). All four genotype classes showed similar capacity to differentiate into MNs at day 8. However, SMA I-derived MN survival was significantly decreased while SMA III- and asymptomatic-derived MN survival was moderately reduced compared to controls at day 27. SMN expression levels and concomitant gem numbers broadly matched SMN2 copy number distribution; SMA I presented the lowest levels, whereas SMA III and asymptomatic showed similar levels. In contrast, PLS3 was significantly upregulated in mixed MN cultures from asymptomatic individuals pinpointing a tissue-specific regulation. Evidence for strong PLS3 accumulation in shaft and rim of growth cones in MN cultures from asymptomatic individuals implies an important role in neuromuscular synapse formation and maintenance. These findings provide strong evidence that PLS3 is a genuine SMA protective modifier.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Heesen, Ludwig UNSPECIFIED UNSPECIFIED UNSPECIFIED Peitz, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Torres-Benito, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoelker, Irmgard UNSPECIFIED UNSPECIFIED UNSPECIFIED Hupperich, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Dobrindt, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Jungverdorben, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Ritzenhofen, Swetlana UNSPECIFIED UNSPECIFIED UNSPECIFIED Weykopf, Beatrice UNSPECIFIED UNSPECIFIED UNSPECIFIED Eckert, Daniela UNSPECIFIED UNSPECIFIED UNSPECIFIED Hosseini-Barkooie, Seyyed Mohsen UNSPECIFIED UNSPECIFIED UNSPECIFIED Storbeck, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Fusaki, Noemi UNSPECIFIED UNSPECIFIED UNSPECIFIED Lonigro, Renata UNSPECIFIED UNSPECIFIED UNSPECIFIED Heller, Raoul UNSPECIFIED UNSPECIFIED UNSPECIFIED Kye, Min Jeong UNSPECIFIED orcid.org/0000-0002-1323-7256 UNSPECIFIED Bruestle, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Brunhilde UNSPECIFIED orcid.org/0000-0003-4051-5191 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-277527
DOI:	10.1007/s00018-015-2084-y
Journal or Publication Title:	Cell. Mol. Life Sci.
Volume:	73
Number:	10
Page Range:	S. 2089 - 2105
Date:	2016
Publisher:	SPRINGER BASEL AG
Place of Publication:	BASEL
ISSN:	1420-9071
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPINAL MUSCULAR-ATROPHY; PLURIPOTENT STEM-CELLS; SURVIVAL MOTOR-NEURON; NEUROMUSCULAR-JUNCTION; MOUSE MODELS; DIRECTED DIFFERENTIATION; SENDAI-VIRUS; SMN PROTEIN; GENE; GENERATION Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27752