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Although nerve cell death is the hallmark of many neurological diseases, the processes underlying this death are still poorly defined. However, there is a general consensus that neuronal cell death predominantly proceeds by regulated processes. Almost 30 years ago, a cell death pathway eventually named oxytosis was described in neuronal cells that involved glutathione depletion, reactive oxygen species production, lipoxygenase activation, and calcium influx. More recently, a cell death pathway that involved many of the same steps was described in tumor cells and termed ferroptosis due to a dependence on iron. Since then there has been a great deal of discussion in the literature about whether these are two distinct pathways or cell type- and insult-dependent variations on the same pathway. In this review, we compare and contrast in detail the commonalities and distinctions between the two pathways concluding that the molecular pathways involved in the regulation of ferroptosis and oxytosis are highly similar if not identical. Thus, we suggest that oxytosis and ferroptosis should be regarded as two names for the same cell death pathway. In addition, we describe the potential physiological relevance of oxytosis/ferroptosis in multiple neurological diseases.

Autism spectrum disorder (ASD) is a neurodevelopmental condition primarily characterized by an impairment of social interaction combined with the occurrence of repetitive behaviors. ASD starts in childhood and prevails across the lifespan. The variability of its clinical presentation renders early diagnosis difficult. Mutations in synaptic genes and alterations of mitochondrial functions are considered important underlying pathogenic factors, but it is obvious that we are far from a comprehensive understanding of ASD pathophysiology. At the synapse, mitochondria perform diverse functions, which are clearly not limited to their classical role as energy providers. Here, we review the current knowledge about mitochondria at the synapse and summarize the mitochondrial disturbances found in mouse models of ASD and other ASD-related neurodevelopmental disorders, like DiGeorge syndrome, Rett syndrome, Tuberous sclerosis complex, and Down syndrome.

Catching primal functional changes in early, ‘very far from disease onset’ (VFDO) stages of Huntington’s disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing in vivo two-photon Ca2+ imaging, we revealed an early pattern of circuit dysregulation in the visual cortex - one of the first regions affected in premanifest Huntington’s disease - characterized by an increase in activity, an enhanced synchronicity and hyperactive neurons. These findings are accompanied by aberrations in animal behavior. We furthermore show that the antidiabetic drug metformin diminishes aberrant Huntingtin protein load and fully restores both early network activity patterns and behavioral aberrations. This network-centered approach reveals a critical window of vulnerability far before clinical manifestation and establishes metformin as a promising candidate for a chronic therapy starting early in premanifest Huntington’s disease pathogenesis long before the onset of clinical symptoms. Huntington’s disease is a devastating brain disorder that causes severe mood disorders, problems with moving, and dementia. Most people develop the condition between their thirties and fifties, and die a decade or two after the symptoms first appear. The disease emerges because of a mutation in the gene for the Huntingtin protein, which leads to neurons slowly dying in the brain. While genetic testing can reveal who carries the faulty gene, no treatment addresses the root of the disorder or prevents it from appearing. Instead, most therapies for Huntington’s disease aim to reduce brain damage once the telltale symptoms are already present. However, the disease-causing protein is expressed early during the life of a patient, which could give it time to damage the brain long before neurons die and the disorder reveals itself. Treatments that start after the first signs of the disease may be too late to reverse the damage. Detecting and preventing early brain changes in people that carry the mutation may thus help to stop the disease from progressing. Here, Arnoux, Willam, Griesche et al. set out to detect the minute changes that the faulty Huntingtin protein may cause in the brain network of young mice with the mutation. State-of-the-art imaging tools helped to examine individual neurons in the brain area that processes visual information. These experiments revealed that a group of brain cells had become hyperactive; once this change had occurred, the mutant animals were less anxious than is typical for mice. Metformin is a drug used to treat diabetes, but it also interferes with a structure that is required to produce the disease-causing Huntingtin protein. Arnoux et al. therefore explored whether the compound could rescue the early brain alterations observed in mutant mice. Adding metformin in the water of the animals for three weeks halted the production of the mutant protein, reversed the brain changes and stopped the abnormal behavior. Further work is now required in humans to confirm that Huntington’s disease starts with a change in the activity of networks in the brain, and to verify that metformin can stop the disorder in its track.

Background Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects. Findings We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays. Conclusions These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. Familial cases of PD are often caused by mutations of PTEN-induced kinase 1 (PINK1) and the ubiquitin ligase Parkin, both pivotal in maintaining mitochondrial quality control. CISD1, a homodimeric mitochondrial iron-sulfur-binding protein, is a major target of Parkin-mediated ubiquitination. We here discovered a heightened propensity of CISD1 to form dimers in Pink1 mutant flies and in dopaminergic neurons from PINK1 mutation patients. The dimer consists of two monomers that are covalently linked by a disulfide bridge. In this conformation CISD1 cannot coordinate the iron-sulfur cofactor. Overexpressing Cisd, the Drosophila ortholog of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in Drosophila reduced climbing ability and lifespan. This was more pronounced with mutant Cisd and aggravated in Pink1 mutant flies. Complete loss of Cisd, in contrast, rescued all detrimental effects of Pink1 mutation on climbing ability, wing posture, dopamine levels, lifespan, and mitochondrial ultrastructure. Our results suggest that Cisd, probably iron-depleted Cisd, operates downstream of Pink1 shedding light on PD pathophysiology and implicating CISD1 as a potential therapeutic target. Parkinson’s disease affects millions of people worldwide, causing progressively worse symptoms like stiffness, tremors and difficulty moving. These issues result from the death of neurons in the brain that produce the neurotransmitter dopamine. While most cases have no known cause, 10 to 15 per cent are due to inherited gene mutations. This includes mutations in the genes that code for the proteins PINK1 and Parkin which are essential for maintaining healthy mitochondria, the powerhouse of the cell. Mutations in this quality control system affect a protein called CISD1, which sits within the outer surface of the mitochondria. CISD1 contains a cluster of iron and sulfur ions, and is involved in regulating iron levels and mitochondrial energy production. However, its role in inherited cases of Parkinson’s disease, particularly those related to mutations in PINK1 and Parkin, is poorly understood. To understand the impact of CISD1, Bitar et al. studied genetically modified fruit flies and dopamine-producing neurons from Parkinson’s patients with PINK1 mutations. This revealed that losing PINK1 activity led to higher levels of CISD1 proteins which lacked the iron-sulfur cluster due to a bond forming between two CISD1 molecules. Reducing levels of the CISD1-equivalent protein in the flies helped to alleviate most of the symptoms caused by PINK1 and Parkin gene mutations, such as difficulties climbing and impaired wing posture. These findings suggest that iron-depleted CISD1 contributes to the symptoms associated with Parkinson’s disease, underscoring its potential as a drug target. Drugs that target CISD1 already exist, which could ease the way for further research. Recent studies have shown that cases of Parkinson’s related to mutations in PINK-1 share features with some non-inherited instances of the disease, suggesting that this approach could potentially benefit many patients.

The glutamate/cystine antiporter system x(c)(-) transports cystine into cells in exchange for glutamate at a ratio of 1:1. It is composed of a specific light chain, xCT, and a heavy chain, 4F2, linked by a disulfide bridge. Intracellularly, cystine is reduced into cysteine, the rate-limiting precursor of glutathione (GSH), an important small molecule antioxidant. Several lines of evidence suggest that the expression of xCT and thereby the presence system x(c)(-) activity plays an important role in the brain. First, it regulates extracellular glutamate concentrations. Second, as brain is prone to oxidative stress due to its high oxygen consumption and lipid content, system x(c)(-) by favoring GSH synthesis, may prevent oxidative damage. Thus, to understand how xCT expression and system x(c)(-) activity are regulated in the central nervous system is of utmost importance. In this review, we will summarize the current knowledge about the molecular basis by which xCT expression and system x(c)(-) activity are regulated in neuronal cell lines, especially the hippocampal cell line, HT22. In addition, we will relate these pathways to findings in other cell types, especially those found in the central nervous system. We will focus on the signaling pathways that modulate the transcription of the xCT gene. Furthermore, we describe possible pathways that modify system x(c)(-) activity beyond the level of xCT transcription, including regulation on the level of membrane trafficking and substrate availability, especially the regulation by glutamate transport through excitatory amino acid transporters.

Parkinson's disease (PD) and the atypical parkinsonian syndromes multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are movement disorders associated with degeneration of the central nervous system. Degeneration of the retina has not been systematically compared in these diseases. This cross-sectional study used spectral-domain optical coherence tomography with manual segmentation to measure the peripapillar nerve fiber layer, the macular thickness, and the thickness of all retinal layers in foveal scans of 40 patients with PD, 19 with MSA, 10 with CBS, 15 with PSP, and 35 age- and sex-matched controls. The mean paramacular thickness and volume were reduced in PSP while the mean RNFL did not differ significantly between groups. In PSP patients, the complex of retinal ganglion cell- and inner plexiform layer and the outer nuclear layer was reduced. In PD, the inner nuclear layer was thicker than in controls, MSA and PSP. Using the ratio between the outer nuclear layer and the outer plexiform layer with a cut-off at 3.1 and the additional constraint that the inner nuclear layer be under 46 µm, we were able to differentiate PSP from PD in our patient sample with a sensitivity of 96% and a specificity of 70%. Different parkinsonian syndromes are associated with distinct changes in retinal morphology. These findings may serve to facilitate the differential diagnosis of parkinsonian syndromes and give insight into the degenerative processes of patients with atypical parkinsonian syndromes.

Current methods of CRISPR-Cas9-mediated site-specific mutagenesis create deletions and small insertions at the target site which are repaired by imprecise non-homologous end-joining. Targeting of the Cas9 nuclease relies on a short guide RNA (gRNA) corresponding to the genome sequence approximately at the intended site of intervention. We here propose an improved version of CRISPR-Cas9 genome editing that relies on two complementary guide RNAs instead of one. Two guide RNAs delimit the intervention site and allow the precise deletion of several nucleotides at the target site. As proof of concept, we generated heterozygous deletion mutants of the kcng4b, gdap1, and ghitm genes in the zebrafish Danio rerio using this method. A further analysis by high-resolution DNA melting demonstrated a high efficiency and a low background of unpredicted mutations. The use of two complementary gRNAs improves CRISPR-Cas9 specificity and allows the creation of predictable and precise mutations in the genome of D. rerio.

Probucol, a hypocholesterolemic compound, is neuroprotective in several models of neurodegenerative diseases but has serious adverse effects in vivo. We now describe the design and synthesis of two new probucol analogues that protect against glutamate-induced oxidative cell death, also known as ferroptosis, in cultured mouse hippocampal (HT22) cells and in primary cortical neurons, while probucol did not show any protective effect. Treatment with both compounds did not affect glutathione depletion but still significantly decreased glutamate-induced production of oxidants, mitochondrial superoxide generation, and mitochondrial hyperpolarization in HT22 cells. Both compounds increase glutathione peroxidase (GPx) 1 levels and GPx activity, also exhibiting protection against RSL3, a GPx4 inactivator. These two compounds are therefore potent activators of GPx activity making further studies of their neuroprotective activity in vivo worthwhile.

Mitochondrial calcium homeostasis involves coordinated uptake via the mitochondrial calcium uniporter (MCU) and efflux through sodium-dependent NCLX (encoded by SLC8B1 ) and/or TMEM65. We investigated TMBIM5, a proposed bidirectional mitochondrial calcium/proton transporter, by generating zebrafish lacking tmbim5 , slc8b1 , plus tmbim5/mcu and tmbim5/slc8b1 double knockouts. Tmbim5-deficient fish exhibited growth impairment, muscle atrophy, and increased brain cell death. tmbim5/mcu double knockouts showed no additive effects, arguing against Tmbim5 functioning as an independent calcium uptake pathway. slc8b1 knockouts had no major phenotype but showed attenuated, although not abolished sodium-dependent mitochondrial calcium efflux. tmbim5/slc8b1 double knockouts showed altered mitochondrial calcium handling with reduced uptake and efflux. Remarkably, brain phenotypes were rescued while muscle dysfunction was exacerbated in double mutants, corresponding to restored mitochondrial membrane potential in brain tissue and decreased calcium levels in muscle. These findings suggest that TMBIM5 functions as an auxiliary calcium efflux pathway cooperating with NCLX in a tissue-specific manner. Tmbim5 and Slc8b1 cooperate in tissue-specific mitochondrial Ca2+ regulation in zebrafish. Genetic analyses show that Tmbim5 is not an independent uptake pathway but acts as an auxiliary Ca2+ efflux mechanism with distinct roles in brain and muscle.