Lamin A/C Mechanotransduction in Laminopathies

Abstract

Mechanotransduction translates forces into biological responses and regulates cell functionalities. It is implicated in several diseases, including laminopathies which are pathologies associated with mutations in lamins and lamin-associated proteins. These pathologies affect muscle, adipose, bone, nerve, and skin cells and range from muscular dystrophies to accelerated aging. Although the exact mechanisms governing laminopathies and gene expression are still not clear, a strong correlation has been found between cell functionality and nuclear behavior. New theories base on the direct effect of external force on the genome, which is indeed sensitive to the force transduced by the nuclear lamina. Nuclear lamina performs two essential functions in mechanotransduction pathway modulating the nuclear stiffness and governing the chromatin remodeling. Indeed, A-type lamin mutation and deregulation has been found to affect the nuclear response, altering several downstream cellular processes such as mitosis, chromatin organization, DNA replication-transcription, and nuclear structural integrity. In this review, we summarize the recent findings on the molecular composition and architecture of the nuclear lamina, its role in healthy cells and disease regulation. We focus on A-type lamins since this protein family is the most involved in mechanotransduction and laminopathies.

Whole‐exome analyses of congenital muscular dystrophy and congenital myopathy patients from India reveal a wide spectrum of known and novel mutations

“…The three‐dimensional (3D) structure of wild‐type (WT) LMNA (Protein Data Bank ID: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6SNZ) [24] protein was extracted from the Protein Data Bank (https://www.rcsb.org). The 3D structures of the other two WT proteins LAMA2 (model_id: 3ef5b25080f4bcba841214f3b99f13cf) and RYR1 (model_id: bd860de330d29ef5d8bf0e222b0a4a74) were extracted from the MODBASE database [25].…”

Nuclear lamin A/C promotes cancer cell survival and lung metastasis without restricting transendothelial migration

“…On the other hand, lamin A/C knockdown melanoma and breast cancer cells exhibited poor long term survival in the lungs as well as reduced growth inside spheroid assemblies grown in 3D environments, two environments that are far less rigid than tissue culture dishes (Barney et al, 2016; Jaiswal et al, 2017). Therefore, the contribution of lamin A/C to cancer cell growth within spheroids is unlikely to involve classical lamin A/C regulated mechanotransduction which predominates cell-extracellular matrix contacts (Donnaloja, Carnevali, Jacchetti, & Raimondi, 2020).…”

Nuclear Mechanotransduction in Skeletal Muscle

“…In line with these physiological roles of A-type lamins, mutations in the LMNA gene cause laminopathies, a heterogeneous group of disorders, including skeletal muscle dystrophies and cardiomyopathies [156,[179][180][181][182]. The severity of the muscle disease is highly variable, the most severe form being the LMNA-related congenital muscular dystrophy [183,184].…”