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Grosjean et al. present a network-aware, self-supervised learning approach for screening neuronal activity dynamics. They demonstrate its applicability across a range of neural interventions.

Scalable CRISPRa screening of cis-regulatory elements in non-cancer cell lines has proved challenging. Here, the authors describe a scalable, CRISPR activation screening framework to identify regulatory element-gene pairs in diverse cell types including cancer cells and neurons.

Inflammation of brain endothelial cells is seen in neurodegenerative conditions and in aging. Here the authors examine the role of astrocytes in blood brain barrier function using an iPSC-derived cell co-culture model.

Leng et al. establish CRISPRi screens in astrocytes to dissect pathways controlling inflammatory reactivity. They uncover two distinct inflammatory reactive signatures that are inversely regulated by STAT3 and validate that these exist in human disease.

This study demonstrates that the extracellular matrix (ECM) of the developing brain stabilizes recently born synapses. The authors identify a microglial metalloprotease that digests the ECM to increase the plasticity of these newborn synapses.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Dräger et al. establish a rapid, scalable platform for iPSC-derived microglia. CRISPRi/a screens uncover roles of disease-associated genes in phagocytosis, and regulators of disease-relevant microglial states that can be targeted pharmacologically.

The nuclear pore complex mediates nucleocytoplasmic transport and consists of an assembly of multiple copies of ∼30 different proteins called nucleoporins. Kampmann and Blobel describe the structure and flexibility of the heptameric Nup84 complex by single-particle, negative-stain EM. They find that the arrangement of β-propeller and α-solenoid folds within the heptamer resembles that of the clathrin triskelion, which has been proposed to share a common evolutionary origin with the heptameric complex.

Genome editing tools can precisely introduce a specified lesion into the DNA, but ultimately rely on the cell’s DNA repair machinery to determine the editing outcome. Here, authors demonstrate how neurons’ unique DNA repair pathways impact the safety, efficiency, and precision of CRISPR edits.

The authors introduce the Neurolipid Atlas, a dynamic resource for the community to gain insight into lipid alterations in neurodegenerative disease, and they leverage the platform to show how cholesterol alterations in astrocytes can dysregulate neuroinflammatory pathways in Alzheimer disease.

Selective vulnerability of particular neuronal cell types is a characteristic of neurodegenerative diseases. Martin Kampmann explores our current understanding of the cellular and molecular mechanisms that lead to selective vulnerability in different diseases.

Samelson et al. report that BRD2 inhibition suppresses SARS-CoV-2 infection in epithelial cells and Syrian hamsters via reducing the transcription of host cell surface receptor ACE2.

The authors developed an adeno-associated virus-based high-throughput in vivo CRISPR screening platform for endogenous mouse brain cell types. Using this platform, they define genes and pathways essential for neuronal survival.

A genome-wide CRISPR interference screen shows that a signalling pathway involving OMA1, DELE1 and the eIF2α kinase HRI relays mitochondrial stress to the cytosol to trigger the integrated stress response.

Many low- and middle-income countries, including The Gambia, had low COVID-19 vaccination coverage during the emergence of the Delta and Omicron variants. Here, the authors perform a prospective household cohort study in the Gambia to investigate the dynamics of SARS-Cov-2 infection in this setting.

Deep mutational scanning reveals that α-synuclein adopts a membrane-bound α-helix conformation with increasing dynamics towards the C terminus. This helical conformation is associated with its cytotoxicity.

The search for effective therapies for neurological disease has been impeded by our limited understanding of the causative molecular and cellular mechanisms. Kampmann describes how new CRISPR-based functional genomics approaches can uncover disease mechanisms and therapeutic targets in neurological diseases.

Polarized fluorescence microscopy is used to investigate the orientation of nucleoporins tagged with GFP within the nuclear pore complex in live yeast and mammalian cells, by analyzing the anisotropy pattern of the fluorophore. This approach can be applied to study other protein assemblies.

Jagne, Jobe et al. assess the SARS-CoV-2-specific immune landscape of people in The Gambia exposed to the pre-Delta variant in July 2021. SARS-CoV-2 infection induces T cell, mucosal, and systemic antibody responses, with variations observed across these immune compartments.

Arrayed CRISPR libraries with each plasmid encoding an array of four non-overlapping single-guide RNAs allow for the efficient genome-wide ablation, activation and epigenetic silencing of human protein-coding genes.

Low-density lipoprotein receptor-related protein 1 (LRP1) is shown to be a critical determinant of tau propagation in the brain.

In this study, Yang et al. show that the mitochondrial-stress-induced cleavage product of DELE1 oligomerizes to generate a signaling platform that activates a cascade of kinases, triggering the integrated stress response.

This protocol describes an RNAi-based high-throughput screening strategy for determining genetic interactions between pairs of mammalian genes; the information obtained is then used to construct genetic interaction maps.

Virus triggered lipophagy is important for flaviviral assembly and coordinated by Aup1 and the ubiquitin conjugating enzyme E2. Here, Lan et al further characterise the interplay between these proteins and how they function to modulate selective autophagy and viral replication.

Development of a biosensor for GPCR trafficking to the lysosome combined with a genome-wide CRISPR screen identified DNAJC13 as a critical regulator of agonist-induced trafficking of the δ-opioid receptor to the lysosome.

Tian et al. conducted a genome-wide CRISPRi/CRISPRa screen in human neurons and uncovered a neuron-specific link among prosaposin, lipofuscin and ferroptosis. The CRISPRbrain data commons enables comparison of gene function across human cell types.

Leng et al. uncover the molecular signature of neuronal subpopulations that are selectively vulnerable to tau aggregation and death early in Alzheimer’s disease in the human entorhinal cortex and other brain regions, validating RORB as a marker.

WDR5 and TBP recruit anaphase-promoting complex to specific transcription start sites in mitosis, initiating a ubiquitin-dependent mechanism that preserves cell identity by linking gene expression and cell division.

Energy metabolism and ATP levels are controlled by an interlocking network of pathways. Here, the authors apply a genome-wide CRISPR screen to define genes that increase or decrease ATP levels to define the “ATPome”, a map of pathways that contribute to cellular ATP regulation.

The human immune system changes with age which impacts pathogen clearance. Here, Vogel et al. probe how CD4 + T-cells from different age groups respond to bacteria and show that activation with staphylococcal antigen induces T cells to become Th1-like cells, whilst stimulation with Bifidobacterium infantis induces a regulatory phenotype.

A combination of shRNA- and CRISPR-Cas9-based gene editing screens, corroborated by a metabolite suppression experiment identifies the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) as the target of the broad-spectrum antiviral compound GSK983.

Combining gene activation and knockout of different genes in the same cell using two different Cas9 enzymes enables the reconstruction of directional dependency.

A small-molecule activator of procaspase 3, 1541, forms chemical fibrils. shRNA screens, caspase proteomics and small-molecule profiling reveal that these fibrils enter cells through endocytosis and promote a distinctive form of cell death.

Single-cell or single-nucleus RNA-sequencing experiments form a basis for biological insights about cell types and states, but they require orthogonal experiments to confirm the functional relevance of their findings. Here the authors discuss options to support such findings and their challenges.