The Nuclear Lamina: Protein Accumulation and Disease

Abstract

Cellular health is reliant on proteostasis-the maintenance of protein levels regulated through multiple pathways modulating protein synthesis, degradation and clearance. Loss of proteostasis results in serious disease and is associated with aging. One proteinaceous structure underlying the nuclear envelope-the nuclear lamina-coordinates essential processes including DNA repair, genome organization and epigenetic and transcriptional regulation. Loss of proteostasis within the nuclear lamina results in the accumulation of proteins, disrupting these essential functions, either via direct interactions of protein aggregates within the lamina or by altering systems that maintain lamina structure. Here we discuss the links between proteostasis and disease of the nuclear lamina, as well as how manipulating specific proteostatic pathways involved in protein clearance could improve cellular health and prevent/reverse disease.

Keywords: autophagy; clearance; lamina; neurodegeneration; premature aging; protein accumulation.

Figure 1

Schematic representation of nuclear lamina structure (as visualized in EM micrographs by Aebi and colleagues [17]). Lamin A/C and Lamin B oligomerize via head-to-tail interactions to form intermediate filaments. These filaments then organize into higher order filaments (green and orange cables) forming a lattice-like pattern under the nuclear envelope that helps to stabilize protein complexes, such as nuclear pore complexes (blue and red structures) and allow for the transport of proteins.

Figure 2

Schematic representation of lamina interactions. The nuclear lamina (red wavy lines) is the meshwork under the inner and outer nuclear membranes (INM and ONM, respectively). The lamina has gaps to permit the placement of nuclear pore complexes (blue). INM proteins, such as nuclear envelope transmembrane (NET) and other lamina-associated proteins (red and green cylinders) penetrate through the lamina to make contact with chromatin (gray spheres). Linker of nucleoplasm to cytoplasm complexes (LINC) formed from nesprins and SAD1/UNC-84 homology (SUN) proteins (orange and blue cylinders, respectively) make contact with actin filaments and microtubules.

Figure 3

Schematic representation of lamin disruption in Hutchinson–Gilford Progeria Syndrome (HGPS) cells. Nuclear lamina structure becomes thickened with lamin A/C proteins (red lines) in addition to progerin (purple lines). This thickening blocks chromatin (gray spheres) interactions with NETs (red and green cylinders) and Lamin B receptors (purple cylinders). Excess SUN proteins may also accumulate in HGPS cells (blue and orange cylinders). Nuclear blebs form that have large gaps in the lamina structure.

Figure 4

Schematic representation of lamina deformation in neurodegenerative diseases (NDs). Aggregates of proteins, such as phospho-Tau (purple lines) lead to the disruption of nuclear pore complexes (blue structure) and loss of nucleo–cytoplasmic transport (red X). This loss of transport leads to accumulations of nuclear proteins (orange lines) and nuclear pore proteins (NUPs—multicolored lines). The accumulation of these aggregates further disrupts the nuclear lamina, facilitates invagination of the nuclear membranes and, ultimately, the loss of heterochromatin (gray spheres).

Figure 5

Linking lamina protein levels with cellular energy sensing. Schematic representation of the link between cellular energy sensing pathways (Sirtuin1 deacetylase (SIRT1) and adenosine mono-phosphate kinase (AMPK)) and mammalian target of rapamycin complex 1 (mTORC1). Increased levels of NAD+ and AMP upregulate SIRT1 and AMPK, respectively leading to downregulation of mTORC1 function. Decreases in growth factors and amino acids also downregulate mTORC1 function. Downstream functions of mTORC1 are indicated. SIRT1 interactions with LC3 are also indicated, leading to the formation of LC3, p62 and HP1 containing vesicles carrying cargo to lysosomes. This also leads to p62 and ALFY binding ubiquitinated cargo for nuclear export.