Loss of Nuclear Envelope Integrity in Aging and Disease

The nuclear envelope (NE) serves as a central organizing unit for the eukaryotic cell. By virtue of its highly selective, semipermeable barrier function, the NE shields the enclosed genetic material, while at the same time ensuring its regulated transcription, replication, and repair. The NE has long been considered to only dismantle during mitosis. However, in recent years it has become clear that in a variety of pathologies, NE integrity becomes compromised during interphase as well. Loss of NE integrity, or briefly NE stress, is manifested in various ways, ranging from a gradual reduction in nucleocytoplasmic transport function, to selective loss and degradation of NE components, and finally to catastrophic rupture events that provoke abhorrent molecular fluxes between the nucleus and cytoplasm. Although cells manage to cope with such forms of NE stress, the different insults to nuclear compartmentalization alter gene regulation and jeopardize genome stability. Hence, loss of NE integrity is emerging as a broad-spectrum pathogenic mechanism. In this review, we discuss the relevance of nuclear compartmentalization and the loss thereof in aging and disease development.