In this perspective, the authors showcase the importance and need for additional investigation of the ubiquitin-dependent regulation of neurodevelopment. They then propose interdisciplinary approaches that will allow improved spatiotemporal understanding of this relationship in the context of basic neuroscience and disease.

Szalay et al. discuss cross-kingdom similarities and differences in 3D chromatin folding in relation to gene regulation, including in bacteria, archaea, mammals and plants. This comparison reveals certain factors as ancestral sculptors of the genome, but also that evolution tolerates considerable variety in genome organization.

Racetam anticonvulsants, such as levetiracetam, are widely prescribed to treat and prevent seizures. Despite decades of clinical use, their mechanism of action remains unclear. Two studies now reveal the structure of the racetam-binding protein SV2A in complex with anticonvulsant drugs, providing insights into their mechanism of action and the physiology of neurotransmission.

Autoantibodies targeting glutamatergic N-methyl-d-aspartic acid receptors (NMDARs) are found in people with anti-NMDAR encephalitis. Two studies reveal that patient-derived autoantibodies are diverse in their epitope binding and modes of action on the NMDAR, providing insights into the mechanisms behind autoantibody-induced NMDAR hypofunction.

Here, the authors provide insights into a splicing quality control mechanism. The Gpl1–Gih35 complex binds to the active site of aberrant spliceosomes, blocks splicing progression and triggers the spliceosome discard pathway.

This study reveals how anamorelin, a superagonist targeting the ghrelin receptor, works compared to other drugs. Structural insights into ligand binding and genetic variations offer a framework for personalized therapies

Gong, Reynolds et al. use cryo-electron microscopy and cryo-electron tomography to uncover how the actin cross-linking factor fascin uses structural flexibility to assemble helical actin filaments into symmetry-mismatched hexagonal bundles.

LYCHOS is a lysosome-localized cholesterol sensor involved in mTORC1 activity regulation. Here, the authors report the three-dimensional structure of LYCHOS bound to cholesterols, revealing the recognition mechanism for this molecule.

Tao et al. show that epidermal growth factor receptor and insulin-like growth factor 1 receptor activation enhances thymidine kinase 1 expression through ERK phosphorylation and deubiquitylation mediated by ubiquitin carboxyl-terminal hydrolase 9X, thus enhancing enzyme activity-dependent DNA synthesis and enzyme activity-independent glycolysis.

The authors show the dimeric structure of human LYCHOS (lysosomal cholesterol signaling), a fusion of a transporter and a G-protein-coupled receptor-like domain. The study uncovers unique transporter and receptor features and proposes a mechanism to couple cholesterol sensing, transport and signaling.

As 2024 closes, we take this opportunity to reflect on the highlights of our 30th anniversary year and consider what the future holds for the field.