The role of the nuclear pore complex in aging of post-mitotic cells

cytoplasm by the nuclear envelope (NE) is critical for eukaryotic cell organization. We have discovered that nuclear pore complexes (NPCs), essential multiprotein channels that mediate molecular trafficking across the NE [1], do not turn over and are extremely long-lived in post-mitotic cells [2]. The lack of a replacement mechanism of NPCs leads to a deterioration of NPC function over time, presumably caused by oxidative damage of NPC scaffold components. Age-dependent nuclear pore deterioration is associated with a loss of cell compartmentalization in old cells. This failure of the nuclear permeability barrier is characterized by the leaking of cytoplasmic proteins into the nucleoplasm. We detected large filaments inside the 'leaky' nuclei of old mouse and rat neurons, which stained with the cytoplasmic protein tubulin [2]. Strikingly, tubulin-positive intranuclear structures have been linked to various neurological disorders including Parkinson's disease [3, 4]. We hypothesize that NPC deterioration might be a general aging mechanism leading to defects in nuclear function, such as the loss of youthful gene expression programs. NPCs are multiprotein assemblies that penetrate the nuclear membrane to form aqueous channels across the NE allowing small molecules to freely diffuse between the nucleoplasm and cytoplasm. In contrast, proteins with molecular masses larger than ~60kD are transported through the NPCs by an active, signal-dependent Impact‐View process [5]. NPCs exhibit 8-fold radial symmetry in the plane of the NE and are composed of multiple copies of ~30 different proteins, called nucleoporins (Nups) [6]. Based on their function at the NE, Nups can be classified into (i) scaffold Nups, which mainly consist of the multiprotein Nup107/160 and Nup93/205 complexes [7] and (ii) peripheral Nups. The latter extend from the membrane-embedded scaffold either into the pore channels or as filaments into the cytoplasm or the nucleoplasm [6, 8, 9]. While the scaffold is thought to provide structural integrity to the highly curved pore membrane, the peripheral Nups, many of which contain phenylalanine-glycine (FG)-repeats, are responsible for establishing the permeability barrier [2] and mediating nuclear trafficking [10]. In dividing cells, NPCs disassemble during mitosis and reassemble into the newly forming nuclei. Our recent results suggest that these multi-protein transport channels do not turnover in post-mitotic cells, where the mitotic renewal of NPCs is absent. While peripheral Nups, like Nup153 and Nup50, are continuously exchanged at the NPC, scaffold nucleoporins, like the Nup107/160 complex, are extremely long-lived and remain incorporated in the nuclear membrane during the entire lifespan …