The factors for the early and late development of midbrain dopaminergic neurons segregate into two distinct evolutionary clusters

Midbrain dopaminergic neurons are responsible for several functions in the reward system, control of emotion, motivation, cognition, and motor behavior. A set of well-characterized transcription factors involved in specification, neurogenesis, and neuronal differentiation determines the fate of these neurons and modulates their survival and maintenance postnatally. Identifying novel molecular connections with these factors might, therefore, lead to a better understanding of physiology as well as dysfunction and degeneration of these neurons in Parkinson's disease. To explore the links between developmental pathways and to identify novel linkages, we examined the correlations of phylogenetic profiles of these factors with those of the entire human proteome. Our analysis revealed two distinct evolutionary pathways comprising the early and late developmental factors and new linkages with these developmental cascades. These results suggest an evolutionary scenario for the development of the midbrain and dopaminergic neurons, with potential novel links to the canonical and non-canonical functions of the transcription factors

Phylogenetic Profiling of Mitochondrial Proteins and Integration Analysis of Bacterial Transcription Units Suggest Evolution of F1Fo ATP Synthase from Multiple Modules

ATP synthase is a complex universal enzyme responsible for ATP synthesis across all kingdoms of life. The F-type ATP synthase has been suggested to have evolved from two functionally independent, catalytic (F1) and membrane bound (Fo), ancestral modules. While the modular evolution of the synthase is supported by studies indicating independent assembly of the two subunits, the presence of intermediate assembly products suggests a more complex evolutionary process. We analyzed the phylogenetic profiles of the human mitochondrial proteins and bacterial transcription units to gain additional insight into the evolution of the F-type ATP synthase complex. In this study, we report the presence of intermediary modules based on the phylogenetic profiles of the human mitochondrial proteins. The two main intermediary modules comprise the α3β3 hexamer in the F1 and the c-subunit ring in the Fo. A comprehensive analysis of bacterial transcription units of F1Fo ATP synthase revealed that while a long and constant order of F1Fo ATP synthase genes exists in a majority of bacterial genomes, highly conserved combinations of separate transcription units are present among certain bacterial classes and phyla. Based on our findings, we propose a model that includes the involvement of multiple modules in the evolution of F1Fo ATP synthase. The central and peripheral stalk subunits provide a link for the integration of the F1/Fo modules

PrePhyloPro: phylogenetic profile-based prediction of whole proteome linkages.

Direct and indirect functional links between proteins as well as their interactions as part of larger protein complexes or common signaling pathways may be predicted by analyzing the correlation of their evolutionary patterns. Based on phylogenetic profiling, here we present a highly scalable and time-efficient computational framework for predicting linkages within the whole human proteome. We have validated this method through analysis of 3,697 human pathways and molecular complexes and a comparison of our results with the prediction outcomes of previously published co-occurrency model-based and normalization methods. Here we also introduce PrePhyloPro, a web-based software that uses our method for accurately predicting proteome-wide linkages. We present data on interactions of human mitochondrial proteins, verifying the performance of this software. PrePhyloPro is freely available at http://prephylopro.org/phyloprofile/

Cholinergic Switch between Two Types of Slow Waves in Cerebral Cortex

Sleep slow waves are known to participate in memory consolidation, yet slow waves occurring under anesthesia present no positive effects on memory. Here, we shed light onto this paradox, based on a combination of extracellular recordings in vivo, in vitro, and computational models. We find two types of slow waves, based on analyzing the temporal patterns of successive slow-wave events. The first type is consistently observed in natural slow-wave sleep, while the second is shown to be ubiquitous under anesthesia. Network models of spiking neurons predict that the two slow wave types emerge due to a different gain on inhibitory versus excitatory cells and that different levels of spike-frequency adaptation in excitatory cells can account for dynamical distinctions between the two types. This prediction was tested in vitro by varying adaptation strength using an agonist of acetylcholine receptors, which demonstrated a neuromodulatory switch between the two types of slow waves. Finally, we show that the first type of slow-wave dynamics is more sensitive to external stimuli, which can explain how slow waves in sleep and anesthesia differentially affect memory consolidation, as well as provide a link between slow-wave dynamics and memory diseases

Cholinergic switch between two types of slow waves in cerebral cortex

31 pages, 5 main figures, 3 supplementary figuresInternational audienceSleep slow waves are known to participate in memory consolidation, yet slow waves occurring under anesthetized states present no positive effects on memory. Here, we shed light onto this paradox, based on a combination of extracellular recordings in vivo, in vitro and computational models. We find two types of slow waves, based on analyzing the temporal patterns of successive slow-wave events. The first type of slow waves is seen during sleep, while the second type prevails in anesthetized states. Network models of spiking neurons predict that the two slow wave types emerge due to a different gain on inhibitory vs excitatory cells and that different levels of spike-frequency adaptation in excitatory cells can account for dynamical distinctions between the two types. This prediction was tested in vitro by varying adaptation strength using an agonist of acetylcholine receptors, which demonstrated a neuromodulatory switch between the two types of slow waves. Finally, we show that the first type of slow-wave dynamics is more sensitive to external stimuli, which can explain how slow waves in sleep and anesthesia differentially affect memory consolidation, as well as provide a link between slow-wave dynamics and memory diseases