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

A fine-grained data set and analysis of tangling in bug fixing commits

Abstract Context: Tangled commits are changes to software that address multiple concerns at once. For researchers interested in bugs, tangled commits mean that they actually study not only bugs, but also other concerns irrelevant for the study of bugs. Objectives: We want to improve our understanding of the prevalence of tangling and the types of changes that are tangled within bug fixing commits. Methods: We use a crowd sourcing approach for manual labeling to validate which changes contribute to bug fixes for each line in bug fixing commits. Each line is labeled by four participants. If at least three participants agree on the same label, we have consensus. Results: We estimate that between 17% and 32% of all changes in bug fixing commits modify the source code to fix the underlying problem. However, when we only consider changes to the production code files this ratio increases to 66% to 87%. We find that about 11% of lines are hard to label leading to active disagreements between participants. Due to confirmed tangling and the uncertainty in our data, we estimate that 3% to 47% of data is noisy without manual untangling, depending on the use case. Conclusions: Tangled commits have a high prevalence in bug fixes and can lead to a large amount of noise in the data. Prior research indicates that this noise may alter results. As researchers, we should be skeptics and assume that unvalidated data is likely very noisy, until proven otherwise

E6AP in the Brain: One Protein, Dual Function, Multiple Diseases

E6-Associated Protein (E6AP), the founding member of the HECT (Homologus to E6AP C terminus) family of ubiquitin ligases, has been gaining increased attention from the scientific community. In addition to its ubiquitin ligase function, our laboratory has also identified steroid hormone receptor transcriptional coactivation as yet another essential function of this protein. Furthermore, it has been established that E6AP has a role in numerous diseases including cancers and neurological syndromes. In this review, we delineate genetic and biochemical knowledge of E6AP and we focus on its role in the pathobiology of neuro-developmental and neuro-aging diseases; bringing to light important gaps of knowledge related to the involvement of its well-studied ligase function versus the much less studied nuclear receptor transcriptional coactivation function in the pathogenesis of these diseases. Tackling these gaps of knowledge could reveal novel possible neuro-pathobiological mechanisms and present crucial information for the design of effective treatment modalities for devastating CNS diseases