Author Correction: Structures of synaptic vesicle protein 2A and 2B bound to anticonvulsants
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Coding principles and mechanisms of serotonergic transmission modes
Serotonin-mediated intercellular communication has been implicated in myriad human behaviors and diseases, yet how serotonin communicates and how the communication is regulated remain unclear due to limitations of available monitoring tools. Here, we report a method multiplexing genetically encoded sensor-based imaging and fast-scan cyclic voltammetry, enabling simultaneous recordings of synaptic, perisynaptic, proximate and distal extrasynaptic serotonergic transmission. Employing this method alongside a genetically encoded sensor-based image analysis program (GESIAP), we discovered that heterogeneous firing patterns of serotonergic neurons create various transmission modes in the mouse raphe nucleus and amygdala, encoding information of firing pulse frequency, number, and synchrony using neurotransmitter quantity, releasing synapse count, and synaptic and/or volume transmission. During tonic and low-frequency phasic activities, serotonin is confined within synaptic clefts due to efficient retrieval by perisynaptic transporters, mediating synaptic transmission modes. Conversely, during high-frequency, especially synchronized phasic activities, or when transporter inhibition, serotonin may surpass transporter capacity, and escape synaptic clefts through 1‒3 outlet channels, leading to volume transmission modes. Our results elucidate a mechanism of how channeled synaptic enclosures, synaptic properties, and transporters collaborate to define the coding principles of activity pattern-dependent serotonergic transmission modes.
Subcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer’s disease
Dystrophic neurites (also termed axonal spheroids) are found around amyloid deposits in Alzheimer’s disease (AD), where they impair axonal electrical conduction, disrupt neural circuits and correlate with AD severity. Despite their importance, the mechanisms underlying spheroid formation remain incompletely understood. To address this, we developed a proximity labeling approach to uncover the proteome of spheroids in human postmortem and mouse brains. Additionally, we established a human induced pluripotent stem cell (iPSC)-derived AD model enabling mechanistic investigation and optical electrophysiology. These complementary approaches revealed the subcellular molecular architecture of spheroids and identified abnormalities in key biological processes, including protein turnover, cytoskeleton dynamics and lipid transport. Notably, the PI3K/AKT/mTOR pathway, which regulates these processes, was activated in spheroids. Furthermore, phosphorylated mTOR levels in spheroids correlated with AD severity in humans. Notably, mTOR inhibition in iPSC-derived neurons and mice ameliorated spheroid pathology. Altogether, our study provides a multidisciplinary toolkit for investigating mechanisms and therapeutic targets for axonal pathology in neurodegeneration.
Brain O-GlcNAcylation: Bridging physiological functions, disease mechanisms, and therapeutic applications
O-GlcNAcylation, a dynamic post-translational modification occurring on serine or threonine residues of numerous proteins, plays a pivotal role in various cellular processes, including gene regulation, metabolism, and stress response. Abundant in the brain, O-GlcNAcylation intricately governs neurodevelopment, synaptic assembly, and neuronal functions. Recent investigations have established a correlation between the dysregulation of brain O-GlcNAcylation and a broad spectrum of neurological disorders and injuries, spanning neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as injuries to the central nervous system (CNS). Manipulating O-GlcNAcylation has demonstrated neuroprotective properties against these afflictions. This review delineates the roles and mechanisms of O-GlcNAcylation in the CNS under both physiological and pathological circumstances, with a focus on its neuroprotective effects in neurological disorders and injuries. We discuss the involvement of O-GlcNAcylation in key processes such as neurogenesis, synaptic plasticity, and energy metabolism, as well as its implications in conditions like Alzheimer’s disease, Parkinson’s disease, and ischemic stroke. Additionally, we explore prospective therapeutic approaches for CNS disorders and injuries by targeting O-GlcNAcylation, highlighting recent clinical developments and future research directions. This comprehensive overview aims to provide insights into the potential of O-GlcNAcylation as a therapeutic target and guide future investigations in this promising field.
Golgi-restored vesicular replenishment retards bone aging and empowers aging bone regeneration
Healthy aging is a common goal for humanity and society, and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration. However, the mechanistic understandings of stem cell senescence and the potential strategies to counteract it remain elusive. Here, we reveal that the aging bone microenvironment impairs the Golgi apparatus thus diminishing mesenchymal stem cell (MSC) function and regeneration. Interestingly, replenishment of cell aggregates-derived extracellular vesicles (CA-EVs) rescues Golgi dysfunction and empowers senescent MSCs through the Golgi regulatory protein Syntaxin 5. Importantly, in vivo administration of CA-EVs significantly enhanced the bone defect repair rate and improved bone mass in aging mice, suggesting their therapeutic value for treating age-related osteoporosis and promoting bone regeneration. Collectively, our findings provide insights into Golgi regulation in stem cell senescence and bone aging, which further highlight CA-EVs as a potential rejuvenative approach for aging bone regeneration.
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