Control of protein degradation pathways by BAG proteins and changes during aging

Many age-related neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and polyglutamine disorders, including Huntington’s disease, are associated with the aberrant formation of protein aggregates. These protein aggregates and/or their precursors are believed to be causally linked to the pathogenesis of such protein conformation disorders, also referred to as proteinopathies. The accumulation of protein aggregates, frequently under conditions of an age-related increase in oxidative stress, implies the failure of protein quality control and the resulting proteome instability as an upstream event of proteinopathies. As aging is a main risk factor of many proteinopathies, potential alterations of protein quality control pathways that accompany the biological aging process could be a crucial factor for the onset of these disorders.rnrnThe focus of this dissertation lies on age-related alterations of protein quality control mechanisms that are regulated by the co-chaperones of the BAG (Bcl-2-associated athanogene) family. BAG proteins are thought to promote nucleotide exchange on Hsc/Hsp70 and to couple the release of chaperone-bound substrates to distinct down-stream cellular processes. The present study demonstrates that BAG1 and BAG3 are reciprocally regulated during aging leading to an increased BAG3 to BAG1 ratio in cellular models of replicative senescence as well as in neurons of the aging rodent brain. Furthermore, BAG1 and BAG3 were identified as key regulators of protein degradation pathways. BAG1 was found to be essential for effective degradation of polyubiquitinated proteins by the ubiquitin/proteasome system, possibly by promoting Hsc/Hsp70 substrate transfer to the 26S proteasome. In contrast, BAG3 was identified to stimulate the turnover of polyubiquitinated proteins by macroautophagy, a catabolic process mediated by lysosomal hydrolases. BAG3-regulated protein degradation was found to depend on the function of the ubiquitin-receptor protein SQSTM1 which is known to sequester polyubiquitinated proteins for macroautophagic degradation. It could be further demonstrated that SQSTM1 expression is tightly coupled to BAG3 expression and that BAG3 can physically interact with SQSTM1. Moreover, immunofluorescence-based microscopic analyses revealed that BAG3 co-localizes with SQSTM1 in protein sequestration structures suggesting a direct role of BAG3 in substrate delivery to SQSTM1 for macroautophagic degradation. Consistent with these findings, the age-related switch from BAG1 to BAG3 was found to determine that aged cells use the macroautophagic system more intensely for the turnover of polyubiquitinated proteins, in particular of insoluble, aggregated quality control substrates. Finally, in vivo expression analysis of macroautophagy markers in young and old mice as well as analysis of the lysosomal enzymatic activity strongly indicated that the macroautophagy pathway is also recruited in the nervous system during the organismal aging process.rnrnTogether these findings suggest that protein turnover by macroautophagy is gaining importance during the aging process as insoluble quality control substrates are increasingly produced that cannot be degraded by the proteasomal system. For this reason, a switch from the proteasome regulator BAG1 to the macroautophagy stimulator BAG3 occurs during cell aging. Hence, it can be concluded that the BAG3-mediated recruitment of the macroauto-phagy pathway is an important adaptation of the protein quality control system to maintain protein homeostasis in the presence of an enhanced pro-oxidant and aggregation-prone milieu characteristic of aging. Future studies will explore whether an impairment of this adaptation process may contribute to age-related proteinopathies.

Management control systems : subcomponents, optimal design and the role of time as a contingency

Management Control System (MCS) research is undergoing turbulent times. For a long time related to cybernetic instruments of management accounting only, MCS are increasingly seen as complex systems comprising not only formal accounting-driven instruments, but also informal mechanisms of control based on organizational culture. But not only have the means of MCS changed; researchers increasingly ap-ply MCS to organizational goals other than strategy implementation.rnrnTaking the question of "How do I design a well-performing MCS?" as a starting point, this dissertation aims at providing a comprehensive and integrated overview of the "current-state" of MCS research. Opting for a definition of MCS, broad in terms of means (all formal as well as informal MCS instruments), but focused in terms of objectives (behavioral control only), the dissertation contributes to MCS theory by, a) developing an integrated (contingency) model of MCS, describing its contingencies, as well as its subcomponents, b) refining the equifinality model of Gresov/Drazin (1997), c) synthesizing research findings from contingency and configuration research concerning MCS, taking into account case studies on research topics such as ambi-dexterity, equifinality and time as a contingency.