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The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory diseases.

Tentorial dural arteriovenous fistulae (DAVF) are rare, have a high risk of hemorrhage, often cannot be obliterated endovascularly, and frequently require microsurgical interruption of the draining vein. We differentiated these fistulae into six types and developed specific operative strategies on the basis of these types. During a 9-year period, 31 patients underwent microsurgical treatment for tentorial fistulae: seven galenic DAVF, eight straight sinus DAVF, three torcular DAVF, three tentorial sinus DAVF, eight superior petrosal sinus DAVF, and two incisural DAVF. The posterior interhemispheric approach was used with galenic DAVF; the supracerebellar-infratentorial approach was used with straight sinus DAVF; a torcular craniotomy was used with torcular DAVF; the supratentorial-infraoccipital approach was used with tentorial sinus DAVF; the extended retrosigmoid approach was used with superior petrosal sinus DAVF; and a pterional or subtemporal approach was used with incisural DAVF. Angiographically, 94% of the fistulae were obliterated completely. Four patients had transient neurological morbidity, none had permanent neurological morbidity; and there was no operative mortality (mean follow-up, 4.2 yr). Tentorial DAVF can be differentiated on the basis of fistula location, dural base, associated sinus, and direction of venous drainage. The operative strategy for each type is almost algorithmic, with each type having an optimum surgical approach and an optimum patient position that allows gravity to retract the brain, open subarachnoid planes, and shorten dissection times. No matter the type, the fistula is treated microsurgically by simple interruption of the draining vein.

Our body expresses sensors to detect pathogens through the recognition of expressed molecules, including nucleic acids, lipids, and proteins, while immune tolerance prevents an overreaction with self and the development of autoimmune disease. Adenosine (A)-to-inosine (I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a post-transcriptional modification that can potentially occur at over 100 million sites in the human genome, mainly in Alu repetitive elements that preferentially form a double-stranded RNA (dsRNA) structure. A-to-I conversion within dsRNA, which may induce a structural change, is required to escape from the host immune system, given that endogenous dsRNAs transcribed from Alu repetitive elements are potentially recognized by melanoma differentiation-associated protein 5 (MDA5) as non-self. Of note, loss-of-function mutations in the ADAR1 gene cause Aicardi–Goutières syndrome, a congenital autoimmune disease characterized by encephalopathy and a type I interferon (IFN) signature. However, the loss of ADAR1 in cancer cells with an IFN signature induces lethality via the activation of protein kinase R in addition to MDA5. This makes cells more sensitive to immunotherapy, highlighting the opposing immune status of autoimmune diseases (overreaction) and cancer (tolerance). In this review, we provide an overview of insights into two opposing aspects of RNA editing that functions as a modulator of the immune system in autoimmune diseases and cancer.

Key Points The membrane protein Nogo-A is a major player in the neurite growth-inhibitory and regeneration-inhibitory effects exerted by myelin in the mammalian brain and spinal cord. In the injured CNS, neutralization or blockade of Nogo-A enhances regeneration, compensatory fibre sprouting and functional recovery. In the intact nervous system, a number of physiological functions of Nogo proteins have been recently discovered, as discussed in this Review. Nogo proteins and the related reticulon (RTN)1-3 proteins consist of a highly conserved, 200-amino acid carboxy-terminal RTN domain and non-homologous amino-terminal extensions of various lengths. The neurite growth-inhibitory protein Nogo-A appeared in evolution for the first time in frogs and is present in all higher vertebrates. Two active sites are present; a Nogo-A-specific domain and a 66-amino acid domain that lies between the transmembrane and intramembrane parts of the RTN domain. Nogo-A is highly enriched in the nervous system, in oligodendrocytes and myelin at adult stages, and in neurons and precursor cells during development. The short proteins Nogo-B and Nogo-C are not inhibitory and occur in various tissues, including the nervous system. Two binding sites are currently known for the Nogo-66 sequence, the Nogo receptor 1 (NgR1) and the membrane protein paired immunoglobulin-like receptor B (PIRB). Both receptors also interact with other ligands, however. The receptor for the Nogo-A specific active site remains to be characterized. Rho activation followed by destabilizing effects on the cytoskeleton are obligatory steps in the postreceptor signalling and effector pathway that leads to the collapse of neurite growth cones. Several additional proteins are associated with what is probably a multisubunit receptor complex for Nogo-A. Nogo-B, by interaction with a Nogo-B receptor (NGBR), influences vascular endothelial cells and smooth muscle cells, which hyperproliferate after vascular lesions in Nogo-A and Nogo-B double knockout mice. The function of Nogo-C is currently still unknown. During CNS development, Nogo-A and its receptors are expressed in cortical precursors and affect their migration. Many projection neurons in the central and peripheral nervous systems express Nogo-A during axonal outgrowth; its neutralization or knockout enhances axonal fasciculation and influences branching. NgR1 and the shorter Nogo forms also have guidance and fasciculation functions in zebrafish, a lower vertebrate. In the adult CNS, oligodendrocyte and myelin Nogo-A suppresses the growth programme of adult neurons, probably by a retrograde action on the cell bodies. Locally, neurite growth is dampened by the growth cone collapsing actions of Nogo-A. Nogo-A thus acts as a stabilizer of the adult CNS neuronal network and wiring. Ablation of Nogo-A or NgR1 accordingly enhances plastic rearrangements of CNS connections, extending the so-called 'critical period' far into adult ages, for example, for visual cortex plasticity. The schizophrenia-like behaviour of Nogo-A knockout mice and the associations found between psychiatric disorders and mutations in the genes encoding Nogo or NgR1 may be based on similar functions. In addition to its cell surface expression, high amounts of Nogo are also present intracellularly. In neurons, its interaction with β-secretase points to a role in the regulation of amyloid precursor protein (APP) processing. Manipulations of Nogo have indicated a structural role for Nogo in the endoplasmic reticulum (ER) and the nuclear membrane. Interactions with proteins involved in cell survival and apoptosis have also been observed. Various approaches aimed at suppressing Nogo-A or NgR1 actions have been used following injury of the adult spinal cord or brain. Acute functional suppression and, with more variable effects, chronic genetic deletion enhance regenerative sprouting and growth of various CNS tract systems. In addition, spared fibre systems have shown enhanced compensatory sprouting; both these processes were associated with substantial improvements of the behavioural recovery of lost functions in rodents and monkeys. These results illustrate the important growth-suppressive role of Nogo-A in the adult mammalian CNS. Nogo proteins inhibit axonal regeneration after injury, but recent studies have shed light on their physiological role in the intact CNS. Martin Schwab reviews the current knowledge of the complex receptor interactions of Nogo proteins and their role in stabilizing CNS wiring during development and in adulthood. The membrane protein Nogo-A was initially characterized as a CNS-specific inhibitor of axonal regeneration. Recent studies have uncovered regulatory roles of Nogo proteins and their receptors — in precursor migration, neurite growth and branching in the developing nervous system — as well as a growth-restricting function during CNS maturation. The function of Nogo in the adult CNS is now understood to be that of a negative regulator of neuronal growth, leading to stabilization of the CNS wiring at the expense of extensive plastic rearrangements and regeneration after injury. In addition, Nogo proteins interact with various intracellular components and may have roles in the regulation of endoplasmic reticulum (ER) structure, processing of amyloid precursor protein and cell survival.

Dandy–Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.

Signal peptide peptidase (SPP) is an ER-resident aspartyl intramembrane protease cleaving proteins within type II-oriented transmembrane segments. Here, we identified the tail-anchored protein Three prime repair exonuclease 1 (TREX1) as a novel substrate of SPP. Based on its DNase activity, TREX1 removes cytosolic DNA acting as a negative regulator of the DNA-sensing cGAS/STING pathway. TREX1 loss-of-function variants cause Aicardi-Goutières syndrome (AGS), a type I interferonopathy. Cleavage of ER-bound TREX1 by SPP releases a cleavage product into the cytosol. Proteolysis depends on sequence determinants within the transmembrane segment and is modulated by different disease-associated TREX1 variants. The AGS-causing T303P variant greatly enhanced susceptibility of TREX1 to intramembrane cleavage accounting for increased degradation and reduced protein stability in AGS patients homozygous for this variant. Other variants within the TREX1 transmembrane segment, P290L, Y305C and G306A, associated with systemic lupus erythematosus variably modulated TREX1 proteolytic processing. Altogether, intramembrane proteolysis can act as a regulator of TREX1 both by controlling its cytosolic localization and mediating its turnover with implications for disease pathogenesis.

Primary microcephaly and megalencephaly are severe brain malformations defined by reduced and increased brain size, respectively. Whether these two pathologies arise from related alterations at the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, leading to cell death. Here, we investigate the consequences of WDR81 loss of function, which causes severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial progenitor cells knocked-out for WDR81 exhibit reduced proliferation rate, subsequently leading to reduced brain size. These proliferation defects are rescued in vivo by expressing a megalencephaly-causing mutant form of Cyclin D2. Our results identify the endosomal machinery as an important regulator of proliferation rates and brain growth, demonstrating that microcephaly and megalencephaly can be caused by opposite effects on the proliferation rate of radial glial progenitors. Mutations in the human WDR81 gene result in severe microcephaly. Carpentieri et al. show that mutation of WDR81, a gene coding for an endosomal regulator, alters intracellular processing of the EGF receptor, leading to reduced proliferation rates of neuronal progenitors and to microcephaly.

While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID-associated phenotypes compared to autism (p = 9.58 × 10(-11), odds ratio = 4.59), dyslexia (p = 3.81 × 10(-18), odds ratio = 14.45), or controls (p = 2.75 × 10(-17), odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4 × 10(-6), odds ratio = 6) or ID (16%, p = 3.55 × 10(-12), odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease. The exosome is responsible for mRNA degradation, which is an important step in the regulation of gene expression. Here the authors report that homozygous missense mutations in the exosome subunit, EXOSC8, may cause neurodegenerative disease in infants through the dysregulation of myelin expression.

A hallmark of systemic lupus erythematosus (SLE), and several related autoimmune diseases, is the presence of autoantibodies against nucleic acids and nucleic acid-binding proteins, as well as elevated type I interferons (IFNs), which appear to be instrumental in disease pathogenesis. Here we discuss the sources and proposed mechanisms by which a range of cellular RNA and DNA species can become pathogenic and trigger the nucleic acid sensors that drive type I interferon production. Potentially SLE-promoting DNA may originate from pieces of chromatin, from mitochondria, or from reverse-transcribed cellular RNA, while pathogenic RNA may arise from mis-localized, mis-processed, ancient retroviral, or transposable element-derived transcripts. These nucleic acids may leak out from dying cells to be internalized and reacted to by immune cells or they may be generated and remain to be sensed intracellularly in immune or non-immune cells. The presence of aberrant DNA or RNA is normally counteracted by effective counter-mechanisms, the loss of which result in a serious type I IFN-driven disease called Aicardi-Goutières Syndrome. However, in SLE it remains unclear which mechanisms are most critical in precipitating disease: aberrant RNA or DNA, overly sensitive sensor mechanisms, or faulty counter-acting defenses. We propose that the clinical heterogeneity of SLE may be reflected, in part, by heterogeneity in which pathogenic nucleic acid molecules are present and which sensors and pathways they trigger in individual patients. Elucidation of these events may result in the recognition of distinct \"endotypes\" of SLE, each with its distinct therapeutic choices.