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In the context of succinate uptake to promote adipose tissue browning, Reddy, Winther et al. show how the directionality of succinate transport across membranes is coupled with metabolic flux-derived changes in pH gradients.

The tumour microenvironment is low in glucose and high in the alternative metabolite lactate, which regulatory T cells are shown here to use, maintaining their ability to suppress effector immune cells.

Oligodendrocytes form myelin sheaths and provide metabolic support to axons. Using in vivo genetic fate tracing in a mouse model of amyotrophic lateral sclerosis (ALS), this study shows that there is extensive degeneration of oligodendrocytes near motor neurons prior to behavioral manifestation of disease. Although oligodendrocytes were regenerated from resident progenitors, they failed to mature and restore myelin, a feature also observed in brain and spinal cord tissue from ALS patients. Selective deletion of ALS-linked mutant SOD1 from the oligodendrocyte lineage greatly delayed disease onset, suggesting that this mutant protein impairs their ability to support motor neurons.

In a short-term study in which hearts from gene-edited pigs were transplanted into two recently deceased human recipients, the hearts were able to function for the duration of the study without signs of rejection and without evidence of pig virus transmission, encouraging further clinical study of cardiac xenotransplantation.

A nucleotide repeat expansion (NRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is linked to multiple neurological conditions. Rothstein and colleagues evaluate the evidence indicating that the NRE causes a loss of C9orf72 function or drives toxic gain-of-function mechanisms and consider the cellular defects through which the mutation drives disease pathology.

A candidate-based genetic screen in Drosophila expressing 30 G₄C₂-repeat-containing RNAs finds that RanGAP, a key regulator of nucleocytoplasmic transport, is a potent suppressor of neurodegeneration; the defects caused by the G₄C₂ repeat expansions can be rescued with antisense oligonucleotides or small molecules targeting the G-quadruplexes.

Recent work has suggested a role for astrocyte dysfunction in the etiology of amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase (SOD1). Lepore et al. show here that transplantation of astrocyte-restricted progenitors in fact improves survival of rats expressing a human ALS-associated SOD1 allele. The rescue effect required the astrocytic glutamate transporter GLT1.

The authors have identified a subpopulation of astrocytes that is enriched in cortical layer V of the mouse cortex and is also present in the human cortex. These cells express Norrin, a protein mutated in a rare neurological degenerative disease called Norrie disease. Norrin acts on neurons to modify their morphology and activity.

Amyotrophic Lateral Sclerosis (ALS) is highly heritable but the mechanisms of sporadic ALS are not fully understood. In this study, the authors identify drivers of variation and disease-relevant changes in the epigenomic profile of iPSC-derived motor neuron lines generated from ALS patients and healthy controls as part of the Answer ALS program.

Hexanucleotide repeat expansion in the intron 1 of the C9ORF72 gene can cause amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). Here the authors use single molecule imaging to show nuclear export and translation of circular repeat-containing C9ORF72 intronic RNA.

Paul Pharoah and colleagues report the results of a large genome-wide association study of ovarian cancer. They identify new susceptibility loci for different epithelial ovarian cancer histotypes and use integrated analyses of genes and regulatory features at each locus to predict candidate susceptibility genes, including OBFC1.

Molecules that inhibit the synthesis of the ataxin 2 protein can ameliorate the effects of two neurodegenerative diseases in mouse models, raising hopes for the success of this approach in clinical trials. See Letters p.362 & p.367

C9orf72 repeat expansion is the major genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, the authors show that transcriptome aberrations commonly found in c9ALS/FTD are a result from defects in cellular RNA surveillance pathways that involve an RNA helicase UPF1.

Disruption of the lactate transporter monocarboxylate transporter 1 (MCT1), which is highly enriched within oligodendroglia and reduced in patients with amyotrophic lateral sclerosis (ALS), causes axon damage and neurodegeneration in animal and cell culture models, suggesting a fundamental role for MCT1 in metabolic support of axons and ALS pathogenesis.

Zhang et al. show that the poly(GA) proteins produced in patients with C9ORF72 repeat expansions cause neurodegeneration and behavioral abnormalities when expressed in mice. The emergence of these phenotypes requires poly(GA) aggregation, and poly(GA) inclusions sequester HR23 proteins involved in proteasomal degradation, as well as proteins involved in nucleocytoplasmic transport.

Structurally polymorphic C9orf72 hexanucleotide repeats cause an impairment in transcriptional processivity and lead to accumulation of truncated repeat-containing transcripts that bind to specific ribonucleoproteins, such as nucleolin, in a conformation-dependent manner resulting in nucleolar stress and C9orf72-linked pathology in amyotrophic lateral sclerosis and frontotemporal dementia.

In this Review, Coyne and Rothstein discuss disruptions to the nuclear pore complex and nucleocytoplasmic transport, which are emerging as pathological mechanisms in multiple neurodegenerative diseases, and consider the effects of these changes on cellular function and their potential for therapeutic targeting.

The recent success of the B-cell-depleting antibody rituximab — originally developed as a lymphoma therapy — in the treatment of rheumatoid arthritis has stimulated considerable interest in the potential of drugs that can modulate B-cell function to treat autoimmune disorders. Browning discusses the role of B cells in a range of such disorders and analyses approaches to therapeutic B-cell manipulation.

A machine learning approach is presented to identify dominant patterns in disease progression in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and Parkinson’s disease. The nonlinearity of ALS progression has important clinical implications.

Answer ALS is a resource of patient-derived iPS cell lines, multi-omic data derived from iPS neurons and longitudinal clinical and smartphone data from over 1,000 patients with ALS. This serves as a foundation to identify distinct disease subgroups.

Georgia Chenevix-Trench and colleagues report meta-analyses of genome-wide association studies identifying six loci newly associated with epithelial ovarian cancer (EOC). They also test variants at the 12 known and 6 new EOC susceptibility loci for association in BRCA1 and BRCA2 mutation carriers.

Investigations into the mechanisms underlying neurodegenerative disease have tended to focus largely on neuronal abnormalities, but it is becoming increasingly evident that astrocytes are important players in these and other neurological disorders. In this Review, the authors describe the normal roles of astrocytes in the brain, and discuss how animal models have provided important insights into the consequences of astrocyte dysfunction.

Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments. In this Review, Ballard and colleagues highlight priority compounds for repurposing for the treatment of Alzheimer disease.

Although it acts as a principal neurotransmitter in the brain, glutamate can be highly destructive if released in excess. Glutamate neurotoxicity has been implicated in stroke, head trauma, multiple sclerosis and neurodegenerative diseases. New research suggests that this abundant amino acid might also be involved the growth of brain tumors. (pages 1010–1015)

The most invasive types of brain tumors can release neurotoxic quantities of glutamate. A new study shows that changing the properties of glutamate receptors can shrink brain tumors in rats (pages 971–978).

Most nerve cells release glutamate as a neurotransmitter, and the protein that packages it into synaptic vesicles has now been identified. This knowledge may one day allow treatment of a variety of diseases that are characterized by aberrant regulation of glutamate.

Microglia are resident myeloid cells of the central nervous system integral for neuroprotective and neurodegenerative processes. Here the authors describe a unique TGF-β dependent molecular and functional microglia signature that distinguishes these cells from other immune and glial cells in the periphery and brain.

The successful immortalization of neural progenitor cells via the overexpression of telomerase prompts several questions for those intending to develop somatic stem cell therapies for neurological disease.

Good–bad binary classifications fail to describe reactive astrocytes in CNS disorders. Here, 81 researchers reach consensus on widespread misconceptions and provide definitions and recommendations for future research on reactive astrocytes.

The authors identify mutations in the MATR3 gene as a cause of ALS and dementia in several families. MATR3 is known to bind the ALS-associated protein TDP-43, and at least one of these mutations alters the efficiency of this binding.