SUMMARY
The self-templating conformations of yeast prion proteins act as epigenetic elements of inheritance. Yeast prions might provide a mechanism for generating heritable phenotypic diversity that promotes survival in fluctuating environments and the evolution of new traits. However, this hypothesis is highly controversial. Prions that create new traits have not been found in wild strains, leading to the perception that they are rare “diseases” of laboratory cultivation. Here we biochemically test ~700 wild strains of Saccharomyces for [PSI+] or [MOT3+], and find these prions in many. They conferred diverse phenotypes that were frequently beneficial under selective conditions. Simple meiotic re-assortment of the variation harboured within a strain readily fixed one such trait, making it robust and prion-independent. Finally, we genetically screened for unknown prion elements. Fully one third of wild strains harboured them. These, too, created diverse, often beneficial phenotypes. Thus, prions broadly govern heritable traits in nature, in a manner that could profoundly expand adaptive opportunities.
Summary
Prions are a paradigm-shifting mechanism of inheritance in which phenotypes are encoded by self-templating protein conformations rather than nucleic acids. Here we examine the breadth of protein-based inheritance across the yeast proteome by assessing the ability of nearly every open reading frame (∼5,300 ORFs) to induce heritable traits. Transient overexpression of nearly 50 proteins created traits that remained heritable long after their expression returned to normal. These traits were beneficial, had prion-like patterns of inheritance, were common in wild yeasts, and could be transmitted to naïve cells with protein alone. Most inducing proteins were not known prions and did not form amyloid. Instead, they are highly enriched in nucleic acid binding proteins with large intrinsically disordered domains that have been widely conserved across evolution. Our data thus establish a common type of protein-based inheritance through which intrinsically disordered proteins can drive the emergence of new traits and adaptive opportunities.
Dopamine (DA) receptors play critical roles in a wide range of behaviours, including sensory processing, motor function, reward and arousal. As such, aberrant DA signalling is associated with numerous neurological and psychiatric disorders. Therefore, understanding the mechanisms by which DA neurotransmission drives intracellular signalling pathways that modulate behaviour can provide critical insights to guide the development of targeted therapeutics. Drosophila melanogaster has emerged as a powerful model with unique advantages to study the mechanisms underlying DA neurotransmission and associated behaviours in a controlled and systematic manner. Many regions in the fly brain innervated by dopaminergic neurons have been mapped and linked to specific behaviours, including associative learning and arousal. Here, we provide an overview of the homology between human and Drosophila dopaminergic systems and review the current literature on the pharmacology, molecular signalling mechanisms and behavioural outcome of DA receptor activation in the Drosophila brain.
Degradation of proteins by the ubiquitin-proteasome pathway (UPP) is critical for the maintenance of protein homeostasis, cell function and survival. While all cells require regulated protein degradation, nerve cells face unique challenges as their highly complex structure and large intracellular space requires special mechanisms to allocate proteasomes to appropriate sub-cellular compartments where protein breakdown occurs. Here we show that the conserved proteasome-binding protein PI31 mediates axonal transport of proteasomes. PI31 binds directly to both proteasomes and dynein light chain LC8-type proteins (DYNLL1/2) and thereby promotes the formation of DYNLL1-PI31-proteasome complexes both in vivo and in vitro. Inactivation of PI31 inhibits proteasome motility in axons of Drosophila neurons, similar to ablation of dDYNLL1/ctp, and it disrupts synaptic protein homeostasis, structure and function. These results indicate that PI31 serves a critical function as an adapter protein to transport proteasomes to the periphery of neurons via microtubule-based motors. Because mutations affecting the activity of PI31 are associated with human neurodegenerative diseases, it is possible that impairment of PI31-mediated axonal transport is the root cause of these disorders.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.