Impaired mechanical response of an EDMD mutation leads to motility phenotypes that are repaired by loss of prenylation

Author:

Zuela Noam1,Zwerger Monika2,Levin Tal1,Medalia Ohad23,Gruenbaum Yosef1ORCID

Affiliation:

1. Department of Genetics, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, 91904, Israel

2. Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland

3. Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben- Gurion University, Beer-Sheva, 84105, Israel

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 C. elegans. We found that an EDMD mutation, L535P, disrupts 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.

Funder

The United States–Israel Binational Science Foundation

Muscular Dystrophy Association

Niedersachsen-Israeli Research Cooperation

European Cooperation in Science and Technology

Israeli Science Foundation

COST

Swiss National Science Foundation

European Molecular Biology Organization

Publisher

The Company of Biologists

Subject

Cell Biology

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