Structural and Mechanical Aberrations of the Nuclear Lamina in Disease

Abstract

The nuclear lamins are the major components of the nuclear lamina in the nuclear envelope. Lamins are involved in numerous functions, including a role in providing structural support to the cell and the mechanosensing of the cell. Mutations in the genes encoding for lamins lead to the rare diseases termed laminopathies. However, not only laminopathies show alterations in the nuclear lamina. Deregulation of lamin expression is reported in multiple cancers and several viral infections lead to a disrupted nuclear lamina. The structural and mechanical effects of alterations in the nuclear lamina can partly explain the phenotypes seen in disease, such as muscular weakness in certain laminopathies and transmigration of cancer cells. However, a lot of answers to questions about the relation between changes in the nuclear lamina and disease development remain elusive. Here, we review the current understandings of the contribution of the nuclear lamina in the structural support and mechanosensing of healthy and diseased cells.

Conquering the Nuclear Envelope Barriers by EBV Lytic Replication

“…Many NE-associated diseases, collectively designated nuclear envelopathies or laminopathies, have been identified. Most of these disorders come from mutations in INM proteins or their interacting partners, diseases including muscular dystrophy, lipodystrophy, neuropathy, and progeria (premature aging) syndromes [ 8 , 9 ]. Diseases may be due to mutations or altered expression of alleles, the mechanical stability of the nucleus, or cell cycle regulation.…”

A Link between Replicative Stress, Lamin Proteins, and Inflammation

“…Different roles for lamins in DNA metabolism were also described, such as regulation of gene expression (by tethering chromatin to the NE, a repressive compartment for transcription, or by binding specific transcription factors). These different functions will not be described here as they have been extensively reviewed [218][219][220]278,279]. We will focus on the role of lamins in genome (in)stability.…”

Design of a 3D printed, motorized, uniaxial cell stretcher for microscopic and biochemical analysis of mechanotransduction

“…In addition, mechanics of the nuclear envelope play a key role in a group of diseases collectively known as laminopathies. These diseases include muscular dystrophies, lipodystrophies, premature aging and cardiomyopathies ( Burke et al, 2001 ; Goebel and Warlo, 2000 ; Stiekema et al, 2020 ; Worman, 2012 ). Therefore, there is a real need to understand the effect of the mechanical environment on cell behavior.…”

“…The LINC complex is an essential protein complex for relaying forces to nucleoskeletal proteins such as Lamin A. Lamin A has over 600 mutations that lead to at least 15 distinct laminopathies ( de Leeuw et al, 2018 ). How one protein can play a role in so many different diseases is unknown, but the effect is generally though to occur through three potential mechanisms: structural, gene regulation, and stem cell lineage determination (recently reviewed in Stiekema et al, 2020 ). The ‘structural hypothesis’ says that lamin mutations alter the structural integrity of the nuclear envelope (NE), thus making the NE less resilient to mechanical stress.…”

“…The ‘structural hypothesis’ says that lamin mutations alter the structural integrity of the nuclear envelope (NE), thus making the NE less resilient to mechanical stress. This results in increase nuclear damage and cell death when cells undergo mechanical stress ( Davidson and Lammerding, 2014 ; Earle et al, 2020 ; Lammerding et al, 2004 , 2004 ; Schreiber and Kennedy, 2013 ; Simon and Wilson, 2013 ; Stiekema et al, 2020 ).…”