The ubiquitin proteasome system in neuropathology

The ubiquitin proteasome system (UPS) orchestrates the turnover of innumerable cellular proteins. In the process of ubiquitination the small protein ubiquitin is attached to a target protein by a peptide bond. The ubiquitinated target protein is subsequently shuttled to a protease complex known as the 26S proteasome and subjected to degradative proteolysis. The UPS facilitates the turnover of proteins in several settings. It targets oxidized, mutant or misfolded proteins for general proteolytic destruction, and allows for the tightly controlled and specific destruction of proteins involved in development and differentiation, cell cycle progression, circadian rhythms, apoptosis, and other biological processes. In neuropathology, alteration of the UPS, or mutations in UPS target proteins may result in signaling abnormalities leading to the initiation or progression of tumors such as astrocytomas, hemangioblastomas, craniopharyngiomas, pituitary adenomas, and medulloblastomas. Dysregulation of the UPS may also contribute to tumor progression by perturbation of DNA replication and mitotic control mechanisms, leading to genomic instability. In neurodegenerative diseases caused by the expression of mutant proteins, the cellular accumulation of these proteins may overload the UPS, indirectly contributing to the disease process, e.g., sporadic Parkinsonism and prion diseases. In other cases, mutation of UPS components may directly cause pathological accumulation of proteins, e.g., autosomal recessive Parkinsonism and spinocerebellar ataxias. Defects or dysfunction of the UPS may also underlie cognitive disorders such as Angelman syndrome, Rett syndrome and autism, and muscle and nerve diseases, e.g., inclusion body myopathy and giant axon neuropathy. This paper describes the basic biochemical mechanisms comprising the UPS and reviews both its theoretical and proven involvement in neuropathological diseases. The potential for the UPS as a target of pharmacological therapy is also discussed

Electronic states of vicinal surfaces

Vicinal surfaces are crystal planes oriented a few degrees off from a high symmetry direction. Such a small deviation (called miscut) from a high symmetry axis leads to a characteristic periodic roughness at the nanoscale, namely atom-height step arrays that separate atomically-flat terraces. The alternating series of “terraces” and “steps” makes electronic properties of vicinal surfaces very peculiar, distinct from those of atomically-flat surfaces. On the one hand, terraces and steps feature atoms with distinct coordination and complex and varied elastic relaxations, influencing their core-level energies. We show how core levels at a vicinal surface exhibit a miscut-dependent stress release, as well as fine structural relaxations, such as faceting. On the other hand, atomic steps create a periodic modulation of the crystal potential, affecting two-dimensional (2-D) surface states of metals. This leads to Bloch scattering of surface electrons by the step lattice, and eventually, to one-dimensional (1-D) quantization by confinement at terraces or step edges. We discuss the occurrence and observation of superlattice scattering and 1"​ D confinement at a vicinal surface, the importance of the atomic nature of the surface state wave function, the dependence on the lattice constant of the step array, and the rich scattering phenomenon that arises in faceted structures and spin-textured bands.Peer reviewe