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By using exome sequencing and extremes of phenotype, McAllister et al. identify rare coding variants with clinical effect in Huntington’s disease. They show that FAN1 nuclease activity slows CAG expansion and is associated with later onset of HD.

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.

New therapies, including RNA-based and gene therapies, are poised to change the therapeutic landscape for Huntington disease. In this article, Hayden and colleagues review the progress that has been made in the past 25 years in developing therapies for this disease and highlight the pitfalls and potential of future treatments.

Amado et al. develop a gene therapy for sporadic ALS using motor neuron-targeting AAVs to deliver RNAi targeting ataxin-2. In a mouse model, survival, strength, and disease-related pathology are improved; and human motor neurons are strongly transduced.

Stable microRNAs (miRNAs) can undergo turnover via target-directed miRNA degradation (TDMD). Here, the authors show that TDMD triggers in non-coding regions degrade miRNAs more effectively than those in coding regions, where translation interferes with this process.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Phosphorylation of the Huntington's disease protein Htt by CK2 leads to Htt nuclear translocation in response to stress. Inhibition of other kinase pathways can restore phosphorylation to hypophosphorylated Htt in Huntington's disease and may lead to a therapeutic strategy.

This article reports a method based on a bifunctional chemical probe called TME and a workflow named RUBICON to capture, enrich and profile endogenous disordered proteins in cells. The method enables a proteome-wide analysis of protein disorder via high-throughput fluorescence and mass spectrometry-based proteomics.

Deuterated amines play a crucial role as building blocks in drug synthesis and in identifying metabolites of novel pharmaceuticals. This study introduces a dual-functional phosphorus-doped iron single-atom catalyst that efficiently enables both reductive amination and deuteration in a one-pot process, utilizing H₂ as the reducing agent and cost-effective D₂O as the deuterium source.

IL-15-driven NK cells mediate anti-tumor immunity, but how IL-15 is negatively regulated remains unclear. Huntington and colleagues find that CIS, a member of the suppressor of cytokine signaling family, suppresses the response to IL-15 and, as a result, CIS-deficient mice are more resistant to cancer metastasis.

GABA transporters expressed in the striatum may affect behaviour. Here the authors investigate the contribution of GABA transporters on astrocytes to the regulation of dopamine release in the striatum, and show decreased expression of GAT-1 and GAT-3 in a mouse model of Parkinsonism.

Dietary restriction promotes healthy brain aging, but the mechanism is unknown. Here, the authors show that OXR1 is upregulated by dietary restriction and confers age-related neuroprotection by maintaining retromer-mediated protein and lipid trafficking.

Jose Florez, Claudia Langenberg, Erik Ingelsson, Inga Prokopenko, Inês Barroso and colleagues perform large-scale association analyses using the Metabochip to gain further insights into the genetic architecture of glucose regulation. They identify 38 new loci influencing 1 or more glycemic traits and show that many of these loci also modify risk of type 2 diabetes.

Manju Kurian and colleagues report heterozygous variants in KMT2B in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance. Their findings highlight a clinically recognizable form of dystonia and demonstrate a crucial role for KMT2B in the physiological control of voluntary movement.

This study supports neurofilament light chain protein (NfL) in both cerebrospinal fluid (CSF) and blood as an early marker of neurodegeneration in Alzheimer’s disease but suggests that NfL in CSF may be better suited than blood for monitoring clinical trial outcomes in symptomatic patients.

Adeno-associated vectors (AAVs) are frequently used for the delivery of genetic cargo but their small packaging capacity is not suitable for delivery of large constructs, including most CRISPR/dCas9-effector systems. Here the authors report a compact dCas9-based repressor system packaged within a single, optimized AAV vector.

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.

Ikaros, Helios and Aiolos are transcription factors involved in lymphocyte development. Here the authors dissect the regulatory role of these Ikaros family members to understand their contribution to NK cell development and functions.

Resources reporting RNA editing sites from brain tissue have been published. Here, the authors provide an atlas of RNA editing events found in the aged and Alzheimer’s disease human brain tissue resulting in changes at protein level.

At UNESCO's celebration of the double helix's fortieth anniversary in Paris last week, nostalgia was overlaid by vigorous optimism about the future of molecular biology.

Bacterial cell growth and division require the coordinated action of enzymes that synthesize and degrade cell wall polymers. Here, the authors identify enzymes that cleave the D-arabinan core of arabinogalactan, an unusual component of the cell wall of Mycobacterium tuberculosis and other mycobacteria.

Single-nucleus transcriptomes of frontal cortex and choroid plexus samples from patients with COVID-19 reveal pathological cell states that are similar to those associated with human neurodegenerative diseases and chronic brain disorders.

Epigenetic clocks based on DNA methylation levels are estimators of chronological age. Here, the authors perform a GWAS of epigenetic aging rates in blood and find SNP variants in the TERT locus associated with increased intrinsic epigenetic age are also associated with longer telomeres.

For decades, research on Alzheimer’s disease and dementia has lacked a unified framework. This Perspective explores the convergence of key amyloid protein oligomerization processes that drive neurodegeneration and cerebrovascular damage, aiming to advance effective diagnosis and treatment of amyloid diseases.

Pathological TDP-43 protein aggregates are a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 pathology alters the morphology of nuclear pore complexes and cause deficits in nucleocytoplasmic transport.

This study assessed COVID-19 social science preprints’ replicability using structured groups. Both beginners and more-experienced participants used a elicitation protocol to make better-than-chance predictions about the reliability of research claims under high uncertainty.

Cerebrospinal fluid neurofilament light (NfL) is a biomarker for neurodegeneration that can also be assessed in blood. Here the authors show in a validation study the potential for plasma NfL as a biomarker for several neurodegenerative diseases.

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.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

This study reports that nuclear speckle constituents have two expression states in cancer correlating with patient survival and HIF-2α functional programs. HIF-2α mediates nuclear speckle association of key genes activated in renal cancer.

Risk of age-related chronic disorders and decrease in resilience is associated with ageing. Here the authors analyse the human blood metabolome and identify metabolites associated with frailty.

A growing body of evidence suggests that many psychiatric illnesses are associated with impaired mitochondrial function. Manji and colleagues review evidence from studies in animal models and humans and discuss strategies for therapeutics aimed at enhancing mitochondrial function in patients with psychiatric disorders.

Mutations in the kinase LRRK2 are associated with Parkinson’s disease. Godena et al. find that disease-associated LRRK2 mutations promote its binding to deacetylated microtubules, and cause defects in axonal transport and Drosophilalocomotor behaviour that can be reversed by enhancing tubulin acetylation.

Tissue-resident memory T (T_RM) cells are distributed throughout the body as relatively sessile populations. Mackay and colleagues find that the tissue in which T_RM cells are generated dictates their properties and is in turn defined according to T_RM-cell-intrinsic sensitivity to signaling via the cytokine TGFβ.

Most neuronal reconstruction software can automatically trace single neuronal morphologies but tracing multiple, densely interwoven neurons is much more challenging. Here the authors develop G-Cut, a computational approach for accurate segmentation of densely interconnected neuron clusters.

There are two main pathways to rid a cell from accumulated protein misfits, the ubiquitin-proteasome system and autophagy. When the ubiquitin proteasome system breaks down, as is the case in a fly model for neurodegenerative disease, autophagy is able to compensate for this loss. HDAC6, a microtubule-associated-histone deacetlyase that interacts with polyubiquitinated proteins, seems to be the link.

This study provides insights into unifying mechanisms that explain the impact of engineered nanomaterials across species and identifies those that underlie differing sensitivities.

Analyses of the proportions of individuals who have completed key levels of schooling across all low- and middle-income countries from 2000 to 2017 reveal inequalities across countries as well as within populations.