PLA2G6-Associated Neurodegeneration (PLAN) is a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the NBIA (Neurodegeneration with Brain Iron Accumulation) group. ...Although the pathogenesis of the disease remains largely unclear, lipid peroxidation seems to play a central role in the pathogenesis. Currently, there is no cure for the disease.
In this work, we examined the presence of lipid peroxidation, iron accumulation and mitochondrial dysfunction in two cellular models of PLAN, patients-derived fibroblasts and induced neurons, and assessed the effects of α-tocopherol (vitamin E) in correcting the pathophysiological alterations in PLAN cell cultures.
Pathophysiological alterations were examined in fibroblasts and induced neurons generated by direct reprograming. Iron and lipofuscin accumulation were assessed using light and electron microscopy, as well as biochemical analysis techniques. Reactive Oxygen species production, lipid peroxidation and mitochondrial dysfunction were measured using specific fluorescent probes analysed by fluorescence microscopy and flow cytometry.
PLAN fibroblasts and induced neurons clearly showed increased lipid peroxidation, iron accumulation and altered mitochondrial membrane potential. All these pathological features were reverted with vitamin E treatment.
PLAN fibroblasts and induced neurons reproduce the main pathological alterations of the disease and provide useful tools for disease modelling. The main pathological alterations were corrected by Vitamin E supplementation in both models, suggesting that blocking lipid peroxidation progression is a critical therapeutic target.
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•PLA2G6 mutations induce increased lipid peroxidation.•PLAN fibroblasts and induced neurons show iron accumulation.•PLAN fibroblasts and induced neurons show altered ΔΨm.•The main pathological alterations were corrected by Vitamin E supplementation.
Amphiphilic glycomimetics encompassing a rigid, undistortable nortropane skeleton based on 1,6-anhydro-l-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion ...complexes with β-cyclodextrin (βCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal β-glucocerebrosidase mutants associated with the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts. The body of work here presented includes the design criteria for the PC prototype, the synthesis of a series of candidates, the characterization of the PC:βCD complexes, the determination of the selectivity profiles toward a panel of commercial and human lysosomal glycosidases, the evaluation of the chaperoning activity in type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (adult neuronopathic) GD fibroblasts, the confirmation of the rescuing mechanism by immunolabeling, and the analysis of the PC:GCase binding mode by docking experiments.
Mitochondrial diseases are considered rare genetic disorders characterized by defects in oxidative phosphorylation (OXPHOS). They can be provoked by mutations in nuclear DNA (nDNA) or mitochondrial ...DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most frequent mitochondrial diseases, principally caused by the m.8344A>G mutation in mtDNA, which affects the translation of all mtDNA-encoded proteins and therefore impairs mitochondrial function.
In the present work, we evaluated autophagy and mitophagy flux in transmitochondrial cybrids and fibroblasts derived from a MERRF patient, reporting that Parkin-mediated mitophagy is increased in MERRF cell cultures. Our results suggest that supplementation with coenzyme Q10 (CoQ), a component of the electron transport chain (ETC) and lipid antioxidant, prevents Parkin translocation to the mitochondria. In addition, CoQ acts as an enhancer of autophagy and mitophagy flux, which partially improves cell pathophysiology. The significance of Parkin-mediated mitophagy in cell survival was evaluated by silencing the expression of Parkin in MERRF cybrids. Our results show that mitophagy acts as a cell survival mechanism in mutant cells.
To confirm these results in one of the main affected cell types in MERRF syndrome, mutant induced neurons (iNs) were generated by direct reprogramming of patients-derived skin fibroblasts. The treatment of MERRF iNs with Guttaquinon CoQ10 (GuttaQ), a water-soluble derivative of CoQ, revealed a significant improvement in cell bioenergetics. These results indicate that iNs, along with fibroblasts and cybrids, can be utilized as reliable cellular models to shed light on disease pathomechanisms as well as for drug screening.
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•MERRF fibroblasts and cybrids show disrupted autophagy flux and Parkin-mediated mitophagy.•Parkin-mediated mitophagy acts a cell survival mechanism in MERRF cybrids cell model.•Coenzyme Q10 acts as an enhancer of autophagy/mitophagy flux, improving cell pathophysiology.•MERRF iNs constitute a new cell model for the screening of potential treatments for MERRF syndrome.
Gaucher disease (GD) is a rare monogenetic disorder leading to dysfunction of acid β-glucosidase (β-glucocerebrosidase; GCase) and accumulation of glucosylceramide in lysosomes, especially in ...macrophages (Gaucher cells). Many of the mutations at the origin of GD do not impair the catalytic activity of GCase, but cause misfolding and subsequent degradation by the quality control system at the endoplasmic reticulum. Pharmacological chaperones (PCs) capable of restoring the correct folding and trafficking of the endogenous mutant enzyme represent promising alternatives to the currently available enzyme replacement and substrate reduction therapies (ERT and SRT, respectively), but unfavorable biodistribution and potential side-effects remain important issues. We have now designed a strategy to enhance the controlled delivery of PCs to macrophages that exploit the formation of ternary complexes between the PC, a trivalent mannosylated β-cyclodextrin (βCD) conjugate and the macrophage mannose receptor (MMR). First, PC candidates with appropriate relative avidities towards the βCD cavity and the GCase active site were selected to ensure efficient transfer of the PC cargo from the host to the GCase active site. Control experiments confirmed that the βCD carrier was selectively recognized by mannose-specific lectins and that the corresponding PC:mannosylated βCD supramolecular complex retained both the chaperoning activity, as confirmed in human GD fibroblasts, and the MMR binding ability. Finally, fluorescence microscopy techniques proved targeting and cellular uptake of the PC-loaded system in macrophages. Altogether, the results support that combined cyclodextrin encapsulation and glycotargeting may improve the efficacy of PCs for GD.
Seventeen Middle Pleistocene crania from the Sima de los Huesos site (Atapuerca, Spain) are analyzed, including seven new specimens. This sample makes it possible to thoroughly characterize a Middle ...Pleistocene hominin paleodeme and to address hypotheses about the origin and evolution of the Neandertals. Using a variety of techniques, the hominin-bearing layer could be reassigned to a period around 430,000 years ago. The sample shows a consistent morphological pattern with derived Neandertal features present in the face and anterior vault, many of which are related to the masticatory apparatus. This suggests that facial modification was the first step in the evolution of the Neandertal lineage, pointing to a mosaic pattern of evolution, with different anatomical and functional modules evolving at different rates.
Objective
Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent.
Method
...Forty‐five patients meeting DSM‐IV and RDC criteria for schizoaffective disorder, groups of patients with 45 matched schizophrenia and bipolar disorder, and 45 matched healthy controls were examined using voxel‐based morphometry (VBM).
Results
Analyses comparing each patient group with the healthy control subjects found that the patients with schizoaffective disorder and the patients with schizophrenia showed widespread and overlapping areas of significant volume reduction, but the patients with bipolar disorder did not. A subsequent analysis compared the combined group of patients with the controls followed by extraction of clusters. In regions where the patients differed significantly from the controls, no significant differences in mean volume between patients with schizoaffective disorder and patients with schizophrenia in any of five regions of volume reduction were found, but mean volumes in the patients with bipolar disorder were significantly smaller in three of five.
Conclusion
The findings provide evidence that, in terms of structural gray matter brain abnormality, schizoaffective disorder resembles schizophrenia more than bipolar disorder.
IntroductionThis umbrella review is the frst to systematically examine psychological trauma as a transdiagnostic risk factor across psychiatric conditions.ObjectivesThis review aimed to be the frst ...to evaluate whether psychological trauma fulflilled criteria as a transdiagnostic risk factor cutting across various diagnostic categories and spectra. Transdiagnosticity will be assessed against the framework of the TRANSD criteria (Fusar-Poli, World Psychiatry 2019; 18 361-362). The paper additionally aimed to analyse the association of psychopathology with specifc trauma type.MethodsWe searched Pubmed, Scopus, and PsycNET databases from inception until 01/05/2021 for systematic reviews/meta-analyses evaluating the association between psychological trauma and at least one diagnosed mental disorder. We re-calculated the odds ratio (OR), then classifed the association as convincing, highly suggestive, suggestive, or weak, based on the number of cases and controls with and without psychological trauma, random-efects p value, the 95% conf- dence interval of the largest study, heterogeneity between studies, 95% prediction interval, small-study efect, and excess significance bias. Additional outcomes were the association between specifc trauma types and specific mental disorders, and a sensitivity analysis for childhood trauma. Transdiagnosticity was assessed using TRANSD criteria. The review was pre-registered in Prospero CRD42020157308 and followed PRISMA/MOOSE guidelines.ResultsFourteen reviews met inclusion criteria, comprising 16,277 cases and 77,586 controls. Psychological trauma met TRANSD criteria as a transdiagnostic factor across diferent diagnostic criteria and spectra. There was highly suggestive evidence of an association between psychological trauma at any time-point and any mental disorder (OR=2.92) and between childhood trauma and any mental disorder(OR=2.90). Regarding specifc trauma types, convincing evidence linked physical abuse (OR=2.36) and highly suggestive evidence linked sexual abuse (OR=3.47) with a range of mental disorders, and convincing evidence linked emotional abuse to anxiety disorders (OR=3.05); there were no data for emotional abuse with other disorders.Image:Image 2:ConclusionsThese fndings highlight the importance of preventing early traumatic events and providing trauma-informed care in early intervention and psychiatric services.Disclosure of InterestNone Declared
Fibromyalgia is a chronic pain syndrome with unknown etiology. Recent studies have shown some evidence demonstrating that oxidative stress may have a role in the pathophysiology of fibromyalgia. ...However, it is still not clear whether oxidative stress is the cause or the effect of the abnormalities documented in fibromyalgia. Furthermore, the role of mitochondria in the redox imbalance reported in fibromyalgia also is controversial. We undertook this study to investigate the role of mitochondrial dysfunction, oxidative stress, and mitophagy in fibromyalgia.
We studied 20 patients (2 male, 18 female patients) from the database of the Sevillian Fibromyalgia Association and 10 healthy controls. We evaluated mitochondrial function in blood mononuclear cells from fibromyalgia patients measuring, coenzyme Q10 levels with high-performance liquid chromatography (HPLC), and mitochondrial membrane potential with flow cytometry. Oxidative stress was determined by measuring mitochondrial superoxide production with MitoSOX and lipid peroxidation in blood mononuclear cells and plasma from fibromyalgia patients. Autophagy activation was evaluated by quantifying the fluorescence intensity of LysoTracker Red staining of blood mononuclear cells. Mitophagy was confirmed by measuring citrate synthase activity and electron microscopy examination of blood mononuclear cells.
We found reduced levels of coenzyme Q10, decreased mitochondrial membrane potential, increased levels of mitochondrial superoxide in blood mononuclear cells, and increased levels of lipid peroxidation in both blood mononuclear cells and plasma from fibromyalgia patients. Mitochondrial dysfunction was also associated with increased expression of autophagic genes and the elimination of dysfunctional mitochondria with mitophagy.
These findings may support the role of oxidative stress and mitophagy in the pathophysiology of fibromyalgia.
Rationale
Clozapine has proven to be superior to other antipsychotic drugs in the treatment of schizophrenia but is under-prescribed due to its potentially severe side effects. Clozapine-induced ...sialorrhea (CIS) is a frequent and extremely uncomfortable side effect, which remains understudied.
Objectives
To examine the prevalence of diurnal and nocturnal CIS in a sample of patients treated with clozapine, and to evaluate its impact on quality of life.
Methods
We conducted a cross-sectional, observational study of 130 patients with schizophrenia spectrum disorders treated with clozapine. The prevalence of CIS was evaluated via specific sialorrhea scales. None of the patients included in the study was receiving a specific treatment for hypersalivation during the study period. Possible associations between sialorrhea and clinical and quality of life variables were analyzed.
Results
Of 130 subjects, 120 (92.3%) suffered from CIS. Eighty-one (62.31%) suffered from diurnal CIS, 115 (88.56%) from nocturnal CIS, and 85 (65.38%) suffered from both. Significant positive associations between quality of life and diurnal CIS (
B
= 0.417;
p
= 2.1e − 6,
R
2
= 0.156) and nocturnal CIS (
B
= 0.411;
p
= 7.7e − 6,
R
2
= 0.139) were detected. Thirty per cent of the subjects reported a moderate to severe negative impact of sialorrhea on their quality of life.
Conclusions
The present study suggests that CIS is highly prevalent in patients with schizophrenia and has an important impact on quality of life in one-third of our sample. Therefore, the inclusion of a systematic evaluation and treatment of CIS in standard clinical practice is highly recommended.
Trial registration
Clinical Trials (
https://clinicaltrials.gov
) under reference NCT04197037.
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