title: Decay in survival motor neuron and plastin 3 levels during differentiation of iPSC-derived human motor neurons.
abstract: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in Survival Motor Neuron 1 (SMN1), leading to degeneration of alpha motor neurons (MNs) but also affecting other cell types. Induced pluripotent stem cell (iPSC)-derived human MN models from severe SMA patients have shown relevant phenotypes. We have produced and fully characterized iPSCs from members of a discordant consanguineous family with chronic SMA. We differentiated the iPSC clones into ISL-1+/ChAT+ MNs and performed a comparative study during the differentiation process, observing significant differences in neurite length and number between family members. Analyses of samples from wild-type, severe SMA type I and the type IIIa/IV family showed a progressive decay in SMN protein levels during iPSC-MN differentiation, recapitulating previous observations in developmental studies. PLS3 underwent parallel reductions at both the transcriptional and translational levels. The underlying, progressive developmental decay in SMN and PLS3 levels may lead to the increased vulnerability of MNs in SMA disease. Measurements of SMN and PLS3 transcript and protein levels in iPSC-derived MNs show limited value as SMA biomarkers.
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London, Egham, TW20 0EX, UK.
authors.forename: María G
authors.initials: MG
authors.lastname: Boza-Morán
authors.affiliation: 1] School of Biological Sciences, Royal Holloway, University of London, Egham, TW20 0EX, UK [2] Department of Genetics and CIBERER U-705, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Martínez-Hernández
authors.affiliation: Department of Genetics and CIBERER U-705, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Bernal
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London, Egham, TW20 0EX, UK.
authors.forename: Klaus
authors.initials: K
authors.lastname: Wanisch
authors.affiliation: Department of Genetics and CIBERER U-705, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Also-Rallo
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London, Egham, TW20 0EX, UK.
authors.forename: Anita
authors.initials: A
authors.lastname: Le Heron
authors.affiliation: Department of Genetics and CIBERER U-705, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Alías
authors.affiliation: Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, Evry Cedex, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Denis
authors.affiliation: Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, Evry Cedex, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Girard
authors.affiliation: Department of Virology, Beckman Research Institute, City of Hope, Duarte, California, USA.
authors.forename: Jiing-Kuan
authors.initials: JK
authors.lastname: Yee
authors.affiliation: Department of Genetics and CIBERER U-705, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Tizzano
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London, Egham, TW20 0EX, UK.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Yáñez-Muñoz
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D002999:Clone Cells; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D016501:Neurites / Q000378:metabolism; D010375:Pedigree; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein; C026742:plastin