title: Impaired mechanical response of an EDMD mutation leads to motility phenotypes that are repaired by loss of prenylation.
abstract: There are roughly 14 distinct heritable autosomal dominant diseases associated with mutations in lamins A/C, including Emery-Dreifuss muscular dystrophy (EDMD). The mechanical model proposes that the lamin mutations change the mechanical properties of muscle nuclei, leading to cell death and tissue deterioration. Here, we developed an experimental protocol that analyzes the effect of disease-linked lamin mutations on the response of nuclei to mechanical strain in living Caenorhabditis elegans We found that the EDMD mutation L535P disrupts the nuclear mechanical response specifically in muscle nuclei. Inhibiting lamin prenylation rescued the mechanical response of the EDMD nuclei, reversed the muscle phenotypes and led to normal motility. The LINC complex and emerin were also required to regulate the mechanical response of C. elegans nuclei. This study provides evidence to support the mechanical model and offers a potential future therapeutic approach towards curing EDMD.
authors.affiliation: Department of Genetics, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Zuela
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Zwerger
authors.affiliation: Department of Genetics, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Levin
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University, Beer-Sheva 84105, Israel.
authors.forename: Ohad
authors.initials: O
authors.lastname: Medalia
authors.affiliation: Department of Genetics, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel gru@vms.huji.ac.il.
authors.forename: Yosef
authors.identifier: 0000-0002-5503-3665
authors.initials: Y
authors.lastname: Gruenbaum
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D034882:Lamins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009068:Movement; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017368:Protein Prenylation / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; C573699:EMR-1 protein, C elegans; D034882:Lamins; D009687:Nuclear Proteins
keywords: C. elegans; Emerin; LINC complex; Laminopathy; Mechanical strain; Muscular dystrophy; Nuclear envelope