Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias

Porphyrias are a group of congenital and acquired diseases caused by an enzymatic impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are described, with different clinical presentations. Acute hepatic porphyrias (AHPs) are characterized by life-threatening acute neuro-visceral crises (acute porphyric attacks, APAs), featuring a wide range of neuropathic (central, peripheral, autonomic) manifestations. APAs are usually unleashed by external “porphyrinogenic” triggers, which are thought to cause an increased metabolic demand for heme. During APAs, the heme precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in the bloodstream and urine. Even though several hypotheses have been developed to explain the protean clinical picture of APAs, the exact mechanism of neuronal damage in AHPs is still a matter of debate. In recent decades, a role has been proposed for oxidative damage caused by ALA, mitochondrial and synaptic ALA toxicity, dysfunction induced by relative heme deficiency on cytochromes and other hemeproteins (i.e., nitric oxide synthases), pyridoxal phosphate functional deficiency, derangements in the metabolic pathways of tryptophan, and other factors. Since the pathway leading to the biosynthesis of heme is inscribed into a complex network of interactions, which also includes some fundamental processes of basal metabolism, a disruption in any of the steps of this pathway is likely to have multiple pathogenic effects. Here, we aim to provide a comprehensive review of the current evidence regarding the mechanisms of neuronal damage in AHPs.

Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy

Krabbe Disease (KD) is an autosomal metabolic disorder that affects both the central and peripheral nervous systems. It is caused by a functional deficiency of the lysosomal enzyme, galactocerebrosidase (GALC), resulting in an accumulation of the toxic metabolite, psychosine. Psychosine accumulation affects many different cellular pathways, leading to severe demyelination. Although there is currently no effective therapy for Krabbe disease, recent gene therapy-based approaches in animal models have indicated a promising outlook for clinical treatment. This review highlights recent findings in the pathogenesis of Krabbe disease, and evaluates AAV-based gene therapy as a promising strategy for treating this devastating pediatric disease.

Genotype- and Age-Dependent Differences in Ultrasound Vocalizations of SPRED2 Mutant Mice Revealed by Machine Deep Learning

Vocalization is an important part of social communication, not only for humans but also for mice. Here, we show in a mouse model that functional deficiency of Sprouty-related EVH1 domain-containing 2 (SPRED2), a protein ubiquitously expressed in the brain, causes differences in social ultrasound vocalizations (USVs), using an uncomplicated and reliable experimental setting of a short meeting of two individuals. SPRED2 mutant mice show an OCD-like behaviour, accompanied by an increased release of stress hormones from the hypothalamic–pituitary–adrenal axis, both factors probably influencing USV usage. To determine genotype-related differences in USV usage, we analyzed call rate, subtype profile, and acoustic parameters (i.e., duration, bandwidth, and mean peak frequency) in young and old SPRED2-KO mice. We recorded USVs of interacting male and female mice, and analyzed the calls with the deep-learning DeepSqueak software, which was trained to recognize and categorize the emitted USVs. Our findings provide the first classification of SPRED2-KO vs. wild-type mouse USVs using neural networks and reveal significant differences in their development and use of calls. Our results show, first, that simple experimental settings in combination with deep learning are successful at identifying genotype-dependent USV usage and, second, that SPRED2 deficiency negatively affects the vocalization usage and social communication of mice.

SmcHD1 underlies the formation of H3K9me3 blocks on the inactive X chromosome in mice

Stable silencing of the inactive X chromosome (Xi) in female mammals is critical for the development of embryos and their postnatal health. SmcHD1 is essential for stable silencing of the Xi, and its functional deficiency results in derepression of many X-inactivated genes. Although SmcHD1 has been suggested to play an important role in the formation of higher order chromatin structure of the Xi, the underlying mechanism is largely obscure. Here we explore the epigenetic state of the Xi in SmcHD1-deficient epiblast stem cells (EpiSCs) and mouse embryonic fibroblasts (MEFs) in comparison with their wild-type counterparts. The results suggest that SmcHD1 underlies the formation of H3K9me3-enriched blocks on the Xi, which, although the importance of H3K9me3 has been largely overlooked in mice, play a critical role in the establishment of the stably silenced state. We propose that the H3K9me3 blocks formed on the Xi facilitate robust heterochromatin formation in combination with H3K27me3, and the substantial loss of H3K9me3 caused by SmcHD1 deficiency leads to aberrant distribution of H3K27me3 on the Xi and derepression of X-inactivated genes.

Gene Replacement in Arabidopsis Reveals Manganese Transport as an Ancient Feature of Human, Plant and Cyanobacterial UPF0016 Proteins

The protein family 0016 (UPF0016) is conserved through evolution, and the few members characterized share a function in Mn2+ transport. So far, little is known about the history of these proteins in Eukaryotes. In Arabidopsis thaliana five such proteins, comprising four different subcellular localizations including chloroplasts, have been described, whereas non-photosynthetic Eukaryotes have only one. We used a phylogenetic approach to classify the eukaryotic proteins into two subgroups and performed gene-replacement studies to investigate UPF0016 genes of various origins. Replaceability can be scored readily in the Arabidopsis UPF0016 transporter mutant pam71, which exhibits a functional deficiency in photosystem II. The N-terminal region of the Arabidopsis PAM71 was used to direct selected proteins to chloroplast membranes. Transgenic pam71 lines overexpressing the closest plant homolog (CMT1), human TMEM165 or cyanobacterial MNX successfully restored photosystem II efficiency, manganese binding to photosystem II complexes and consequently plant growth rate and biomass production. Thus AtCMT1, HsTMEM165, and SynMNX can operate in the thylakoid membrane and substitute for PAM71 in a non-native environment, indicating that the manganese transport function of UPF0016 proteins is an ancient feature of the family. We propose that the two chloroplast-localized UPF0016 proteins, CMT1 and PAM71, in plants originated from the cyanobacterial endosymbiont that gave rise to the organelle.

The Denied Pleasure of Eating: A Qualitative Study with Functionally Diverse People in Spain

This qualitative study explores the difficulties in experiencing eating-derived pleasure within a group of functionally diverse people, based on personal interviews and Grounded Theory. Understanding the feelings and subjective experiences of functionally diverse people can help develop new approaches to address their loss of pleasure and motivation regarding food intake. The study included 27 participants, aged between 18 and 75 years, all of whom had a functional deficiency that affected the occupational aspects of the eating process. Interviews were conducted in clinical settings and several centres for differently abled people. Four main themes emerged from the analysis: eating through obligation; fear of eating; the social life of food; and the importance of the taste and visual aesthetics of food. These themes underscore the importance of taking into account the phenomenological experiences of pleasure in the eating process.

Histamine H1 receptor deletion in cholinergic neurons induces sensorimotor gating ability deficit and social impairments in mice

Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H1 receptor (H1R) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H1R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H1R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H1R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.

The relationship of folate deficiency, hyperhomocysteinemia and glutathione metabolism in hypertensive patients

Hypertension (HTN) is often accompanied by folic acid (FA) deficiency and hyperhomocysteinemia (HHcy). Reduced glutathione (GSH) and dependent enzymes determine the state of cellular antioxidant and redox systems in cardiovascular pathology. The aim of our work is to assess the relationship between the status of FA and the presence of HHcy with enzymes of glutathione metabolism and the redox state of erythrocyte glutathione in HTN. Design and methods. In blood plasma samples from 43 HTN patients admitted to the clinic of Pavlov University, the concentration of FA and total homocysteine (oHcy) was determined. We also evaluated the level of GSH, the activity of glutathione peroxidase and glutathione reductase (GR) in erythrocytes. Results. In the whole group, GR activity positively correlated with the concentration of FA (R = 0,415; p = 0,001). A significant decrease in GR activity (U/g Hb) was found in the subgroup with the low level of FA [0,8 (0,5–1,1)] compared with the subgroup without a FA deficiency [1,2 (0,9–2,0)]. The GSH level (μM/g Hb) was also lower (p < 0,018) in the subgroup with FA deficiency [1,3 (0,9–2,1)] compared with the subgroup with normal FA levels [1,8 (1,5–4,6)]. A significant decrease in the level of GSH and GR activity in the subgroup with HHcy was found compared with the corresponding parameters in the subgroup without HHcy. However, even in the absence of HHcy patients with FA deficiency demonstrated a significant decrease in GR activity compared to patients without FA deficiency. In this case, GR positively correlated with FA (R = 0,564; p = 0,03). Conclusions. The deficiency of FA can increase the deficiency of GR activity, regardless of the level of oHcy. The indicator of GR activity in erythrocytes can be considered as a possible marker of functional deficiency of FA in the absence of HHcy.

The impact of C-Tactile Low threshold mechanoreceptors on affective touch and social interactions in mice

Affective touch is necessary for proper neurodevelopment and sociability. However, it is still unclear how the neurons innervating the skin detect affective and social behaviours. To clarify this matter, we targeted a specific population of somatosensory neurons in mice, named C-low threshold mechanoreceptors (C-LTMRs), that appears particularly well suited physiologically and anatomically to perceive affective and social touch but whose contribution to these processes has not yet been resolved. Our observations revealed that C-LTMRs functional deficiency from birth induced social isolation and reduced tactile interactions in adults. Conversely, transient increase in C-LTMRs excitability in adults using chemogenetics was rewarding, temporally promoted touch seeking behaviours and thus had pro-social effects on group dynamics. This work provides the first empirical evidence that specific peripheral inputs alone can drive complex social behaviour, demonstrating the existence of a specialised neuronal circuit originating from the skin wired to promote interaction with other individuals.