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Engineering human microglia with a Down-syndrome-linked myeloid gene variant resists tau-induced dysfunction and protects neurons in chimeric brains, offering proof of concept for transformative microglial replacement therapies in Alzheimer’s disease.

Aaron Gitler, Robert Farese Jr. and colleagues identify the RNA lariat debranching enzyme Dbr1 as a potent suppressor of TDP-43 toxicity in yeast. They further show that Dbr1 knockdown reduces TDP-43 toxicity in mammalian cells, identifying this enzyme as a possible therapeutic target in amyotrophic lateral sclerosis and other diseases marked by TDP-43 accumulation.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

A screen now identifies a protein that regulates degradation of mutant huntingtin, which causes Huntington's disease, and manipulations show that promoting clearance of the toxic protein itself may be sufficient to halt disease.

Abnormal accumulations of toxic proteins are often found in degenerating neurons. Here, Aron and colleagues show that non-enzymatic function of deubiquitinase Usp12 can mitigate neuronal cell death caused by mutant Huntingtin by inducing neuronal autophagic function.

Inclusions containing TDP43 are linked to pathologies in several neurodegenerative diseases such as ALS and FTD. Pathogenic TDP43 mutations are now found to shorten the protein's half-life in individual neurons. Stimulating autophagy with inhibitors improves TDP43 clearance and localization.

Monitoring the half-life of mutant huntingtin protein reveals how specific neurons are more susceptible to its toxic effects and to Huntington's disease.

In this paper, Korb and colleagues find that Arc can shuttle in and out of the nucleus in an activity-dependent manner. The authors further demonstrate that the nuclear translocation of Arc participates in homeostatic plasticity by promoting the formation of PML nuclear bodies, which in turn decreases GluA1 transcription, eventually contributing to the downscaling of synaptic strength.

Conformation-specific antibodies and longitudinal tracking of individual neurons in situ identifies a toxic monomer species linked to Huntington's disease.

Chou et al. generate transdifferentiated human neurons from fibroblasts from young or aged individuals and patients with Alzheimer’s disease. Studies of endolysosomes and proteostasis suggest a role for lysosomal quality control in Alzheimer’s disease pathology.

Risk variants for ALS and FTD in the synaptic gene UNC13A increase the expression of an UNC13A cryptic exon in neurons with TDP-43 depletion.

Cell death is a critical process in health and disease, yet available markers record later stages of cell death once a cell has already begun to decompose. Here the authors show the use of a genetically encoded calcium indicator that demarcates an irreversible stage of cell death earlier than previously possible.

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.

There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.

Lasting synaptic plasticity requires precise local regulation of protein expression. A recent paper reports that the postsynaptic activity–induced arc mRNA is a target for rapid degradation by the 'nonsense-mediated decay' pathway.

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.

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.

A secure framework that harmonizes storage and querying of clinical and genetic data using blockchain technology was developed to support combined genotype–phenotype queries, improving transparency into how and when health information is used.

Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.

Regulation of gene expression and splicing are thought to be tissue-specific. Here, the authors obtain genomic and transcriptomic data from putamen and substantia nigra of 117 neurologically healthy human brains and find that splicing eQTLs are enriched for neuron-specific regulatory information.

The Huntington's disease (HD) induced pluripotent stem cell (iPSC) consortium describe the combined use of differentiated patient-derived iPSCs and systems biology to discover underlying mechanisms in HD. They identify neurodevelopmental deficits in HD cells that can be corrected in cells and in vivo with a small molecule.

Nancy Bonini and colleagues performed a genome-wide yeast screen for modifiers of TDP-43 toxicity and identified genes in RNA metabolism, including several RNA-binding proteins with connections to stress granules. They determined that therapeutic modulation of stress granule–associated eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models in flies and primary mammalian neurons.

Could similar changes in superoxide dismutase 1 (SOD1) underlie both familial and sporadic amyotrophic lateral sclerosis (ALS)? A new study finds that wild-type SOD1 from sporadic ALS tissues shows conformational changes similar to those seen in familial ALS and may be pathogenic as a result of the same mechanism.

Gabriela Novak et al. utilize scRNA-seq to investigate expression profiles in iPSC-derived midbrain dopaminergic neurons from Parkinson’s disease patients or healthy controls. Their results suggest a core molecular network associated with Parkinson’s disease pathology, and provide a future resource for investigation of this critical disorder.

Jeremy Linsley, Atmiyata Tripathi et al. optimise culturing techniques and develop a microscopy platform and that can automatically image and track single neurons within organotypic slices for up to a three-week period. Using a model of polyQ neurodegeneration, they show that this method can assess longitudinal cell changes with high accuracy.