Enzymatic catalysts capable of disentangling potentially disease-causing protein aggregates have been proposed as a therapeutic solution to neurodegenerative disease. Given that all other forms of non-animal life already have these enzymes, it raises the question of why have humans lost the ability to express these potentially beneficial remedies? The answer to animal-specific loss of protein disentangling enzymes may lie in a potential beneficial role of protein aggregates that is incompatible with the presence of potent enzymes capable of destroying them. In this grant, the investigators will test this hypothesis in a comprehensive way by using the complementary features of two powerful genetic model organisms. Newly identified and potentially more subtle enzymatic regulators of protein aggregation will be identified using the yeast model system and then tested for regulation of the protein aggregates recently found in young, healthy embryos of the nematode worms. This grant will carry out a comprehensive examination of protein aggregates and their dedicated enzymatic regulators and seek to understand how they may serve as novel mechanisms to control key events in early animal development including the storage of key developmental proteins that can be released as required. To further connections between science and society, funds will also be used to develop new initiatives that expose middle school students, teachers and undergraduates to methods for studying genomes and genome evolution as well as the genetic analysis of complex traits.
Although processes of amyloid formation and inheritance are historically studied because of their associated pathologies, normal physiological roles of amyloid-type aggregates are becoming more appreciated with many examples of beneficial amyloid functions in species ranging from yeast to mammals. Interestingly, the potent Hsp100-type disaggregase, which plays a role in aggregate clearance, is absent in animal genomes. Thus, the central hypothesis of this grant is that broad-spectrum disaggregases like the Hsp100 class are incompatible with the evolution of animal multicellularity because protein aggregation and the maintenance of the amyloid form of specific proteins are required for animal development. Consistent with this, a surprising abundance of amyloid-type aggregates is shown during early development of C. elegans embryos. The objective of this grant is to characterize the role of amyloid aggregates during development and to investigate their regulation by identifying and characterizing developmentally expressed candidate animal disaggregases. To accomplish this objective, research plan capitalizes on complementary and synergistic experimental advantages of C. elegans and S. cerevisiae. Experiments will 1) analyze the function and regulation of developmentally important amyloids by characterizing candidate endogenous animal disaggregase activities, 2) characterize key aggregation-prone proteins and their regulators in C. elegans development and 3) determine the function of C. elegans amyloidized protein aggregates. Taken together, this grant will examine how amyloids and their dedicated disaggregases serve as novel regulators of key events in early animal development including storage, propagation and distribution of maternal and zygotically synthesized proteins.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
