Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

Laminopathies are a group of rare genetic disorders with heterogeneous clinical phenotypes such as premature aging, cardiomyopathy, lipodystrophy, muscular dystrophy, microcephaly, epilepsy, and so on. The cellular phenomena associated with laminopathy invariably show disruption of nucleoskeleton of lamina due to deregulated expression, localization, function, and interaction of mutant lamin proteins. Impaired spatial and temporal tethering of lamin proteins to the lamina or nucleoplasmic aggregation of lamins are the primary molecular events that can trigger nuclear proteotoxicity by modulating differential protein–protein interactions, sequestering quality control proteins, and initiating a cascade of abnormal post‐translational modifications. Clearly, laminopathic cells exhibit moderate to high nuclear proteotoxicity, raising the question of whether an imbalance in nuclear proteostasis is involved in laminopathic diseases, particularly in diseases of early aging such as HGPS and laminopathy‐associated premature aging. Here, we review nuclear proteostasis and its deregulation in the context of lamin proteins and laminopathies. In various laminopathic diseases, mutant lamin proteins, especially lamin A (LMNA), become mislocalized and aggregate in the nucleoplasm. LMNA aggregates lead to nuclear deformation, disrupt nuclear proteostasis by sequestering nuclear proteins, and deregulate stress response pathways. Deregulation of nuclear proteostasis by mutant LMNA leads to loss of nuclear protein quality control, DNA damage, altered chromatin dynamics, impaired transcription, and other pathological features in laminopathic diseases.