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.

Cell Biology of theCaenorhabditis elegansNucleus

“…Interestingly, a recent study measured mechanical responses to external physical tension and found a significant increase in hypodermal nuclear stiffness in animals depleted for UNC-84 (Zuela et al 2016). Ectopic expression of LMN-1 carrying a L535P substitution, which mimics an Emery-Dreifuss muscular dystrophy mutation in the human LMNA gene, extends the effects of UNC-84 depletion on nuclear stiffness to include muscles (Zuela et al 2016).…”

“…In an effort to understand the underlying mechanism of various laminopathies, a number of disease-related lamin mutations have been introduced into C. elegans. Many of these mutations disrupted C. elegans LMN-1 oligomerization in vitro and lamin function in vivo (Wiesel et al 2008;Bank et al 2011Bank et al , 2012Mattout et al 2011;Zuela et al 2016). For example, LMN-1DK46, which corresponds to the deletion of lysine 32 in the rod domain of lamin A/C in Emery-Dreifuss muscular dystrophy patients, causes defects in the lateral assembly of LMN-1 dimers and results in abnormal muscle structure and motility in the worm .…”

“…For example, LMN-1DK46, which corresponds to the deletion of lysine 32 in the rod domain of lamin A/C in Emery-Dreifuss muscular dystrophy patients, causes defects in the lateral assembly of LMN-1 dimers and results in abnormal muscle structure and motility in the worm . Other lmn-1 mutations associated with Emery-Dreifuss muscular dystrophy affect muscle-specific gene expression (Mattout et al 2011) and have tissue-specific effects on mechanical properties of the nucleus (Zuela et al 2016). The Zuela et al study is especially significant because it examined the mechanical properties of the nucleus in an intact organism, unlike previous studies that were done using tissue culture.…”

Global transcriptional changes caused by an EDMD mutation correlate to tissue specific disease phenotypes inC. elegans

“…Restoring proper muscle nuclear response rescued disease phenotypes in these animals. 20 However, this hypothesis does not fully explain how a globally expressed mutation can have such a tissue specific effect, as not all muscle diseases caused by lamin mutations affect the exact same muscle sub-types. Furthermore, expressing the Y59C EDMD linked mutation did not affect muscle nuclear mechanical response, but rather the transcription of muscle specific developmentally expressed genes.…”

“…Furthermore, expressing the Y59C EDMD linked mutation did not affect muscle nuclear mechanical response, but rather the transcription of muscle specific developmentally expressed genes. 20,21 Also, the skin, which is under constant mechanical tension, has no apparent phenotypes in this group of diseases. The many nuclear roles attributed to lamins are most likely mediated through their interactions with a variety of inner nuclear membrane proteins, which are differentially expressed within tissues.…”