In recent years, genome-wide analyses of patients have resulted in the identification of a number of neurodevelopmental disorders. Several of them are caused by mutations in genes that encode for RNA-binding proteins. One of these genes is PURA, for which in 2014 mutations have been shown to cause the neurodevelopmental disorder PURA syndrome. Besides intellectual disability (ID), patients develop a variety of symptoms, including hypotonia, metabolic abnormalities as well as epileptic seizures. This review aims to provide a comprehensive assessment of research of the last 30 years on PURA and its recently discovered involvement in neuropathological abnormalities. Being a DNA- and RNA-binding protein, PURA has been implicated in transcriptional control as well as in cytoplasmic RNA localization. Molecular interactions are described and rated according to their validation state as physiological targets. This information will be put into perspective with available structural and biophysical insights on PURA’s molecular functions. Two different knock-out mouse models have been reported with partially contradicting observations. They are compared and put into context with cell biological observations and patient-derived information. In addition to PURA syndrome, the PURA protein has been found in pathological, RNA-containing foci of patients with the RNA-repeat expansion diseases such as fragile X-associated tremor ataxia syndrome (FXTAS) and amyotrophic lateral sclerosis (ALS)/fronto-temporal dementia (FTD) spectrum disorder. We discuss the potential role of PURA in these neurodegenerative disorders and existing evidence that PURA might act as a neuroprotective factor. In summary, this review aims at informing researchers as well as clinicians on our current knowledge of PURA’s molecular and cellular functions as well as its implications in very different neuronal disorders.
Summary The neural crest (NC) gives rise to a multitude of fetal tissues, and its misregulation is implicated in congenital malformations. Here, we investigated molecular mechanisms pertaining to NC-related symptoms in Bohring-Opitz syndrome (BOS), a developmental disorder linked to mutations in the Polycomb group factor Additional sex combs-like 1 ( ASXL1 ). Genetically edited human pluripotent stem cell lines that were differentiated to NC progenitors and then xenotransplanted into chicken embryos demonstrated an impairment of NC delamination and emigration. Molecular analysis showed that ASXL1 mutations correlated with reduced activation of the transcription factor ZIC1 and the NC gene regulatory network. These findings were supported by differentiation experiments using BOS patient-derived induced pluripotent stem cell lines. Expression of truncated ASXL1 isoforms (amino acids 1–900) recapitulated the NC phenotypes in vitro and in ovo , raising the possibility that truncated ASXL1 variants contribute to BOS pathology. Collectively, we expand the understanding of truncated ASXL1 in BOS and in the human NC.
Whereas the effect of vagal nerve stimulation on emotional states is well established, its effect on cognitive functions is still unclear. Recent rodent studies show that vagal activation enhances reinforcement learning and neuronal dopamine release. The influence of vagal nerve stimulation on reinforcement learning in humans is still unknown. Here, we studied the effect of transcutaneous vagal nerve stimulation on reinforcement learning in eight long-standing seizure-free epilepsy patients, using a well-established forced-choice reward-based paradigm in a cross-sectional, within-subject study design. We investigated vagal nerve stimulation effects on overall accuracy using non-parametric cluster-based permutation tests. Further, we modelled sub-components of the decision process using drift-diffusion modelling. We found higher accuracies in the vagal nerve stimulation condition compared to sham stimulation. Modelling suggests a stimulation-dependent increase of reward sensitivity and shift of accuracy-speed trade-offs towards maximizing rewards. Moreover, vagal nerve stimulation was associated with increased non-decision times suggesting enhanced sensory or attentional processes. No differences of starting bias were detected for both conditions. Accuracies in the extinction phase were higher in later trials of the vagal nerve stimulation condition suggesting a perseverative effect compared to sham. Together, our results provide first evidence of causal vagal influence on human reinforcement learning and might have clinical implications for usage of vagal stimulation in learning deficiency.
The vagus nerve constitutes a key link between the autonomic and the central nervous system. Previous studies provide evidence for the impact of vagal activity on distinct cognitive processes including functions related to social cognition. Recent studies in animals and humans show that vagus nerve stimulation is associated with enhanced reward-seeking and dopamine-release in the brain. Social interaction recruits similar brain circuits to reward processing. We hypothesize that vagus nerve stimulation (VNS) boosts rewarding aspects of social behavior and compare the impact of transcutaneous VNS (tVNS) and sham stimulation on social interaction in 19 epilepsy patients in a double-blind pseudo-randomized study with cross-over design. Using a well-established paradigm, i.e., the prisoner’s dilemma, we investigate effects of stimulation on cooperative behavior, as well as interactions of stimulation effects with patient characteristics. A repeated-measures ANOVA and a linear mixed-effects model provide converging evidence that tVNS boosts cooperation. Post-hoc correlations reveal that this effect varies as a function of neuroticism, a personality trait linked to the dopaminergic system. Behavioral modeling indicates that tVNS induces a behavioral starting bias towards cooperation, which is independent of the decision process. This study provides evidence for the causal influence of vagus nerve activity on social interaction.
The RNA-binding protein PURA has been implicated in the rare, monogenetic, neurodevelopmental disorder PURA Syndrome. PURA binds both DNA and RNA and has been associated with various cellular functions. Only little is known about its main cellular roles and the molecular pathways affected upon PURA depletion. Here, we show that PURA is predominantly located in the cytoplasm, where it binds to thousands of mRNAs. Many of these transcripts change abundance in response to PURA depletion. The encoded proteins suggest a role for PURA in immune responses, mitochondrial function, autophagy and processing (P)-body activity. Intriguingly, reduced PURA levels decrease the expression of the integral P-body components LSM14A and DDX6 and strongly affect P-body formation in human cells. Furthermore, PURA knockdown results in stabilization of P-body-enriched transcripts, whereas other mRNAs are not affected. Hence, reduced PURA levels, as reported in patients with PURA Syndrome, influence the formation and composition of this phase-separated RNA processing machinery. Our study proposes PURA Syndrome as a new model to study the tight connection between P-body-associated RNA regulation and neurodevelopmental disorders.
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