Chen Qiao

Astrocyte pathology is increasingly recognized as a key factor in the pathogenesis of major depressive disorder (MDD), where disrupted glutamate clearance and impaired neuron-glia interactions contribute to synaptic dysfunction. However, the molecular mechanisms leading to astrocyte loss remain largely undefined. Mitochondrial dysfunction is a hallmark of MDD, yet most studies have focused on neuronal mitochondria, leaving astrocytic mitochondrial dynamics insufficiently investigated. Here, we identify mitofusin-2 (MFN2)–associated astrocyte dysfunction in depression. SMART-seq profiling of hippocampal astrocytes from chronic social defeat stress (CSDS) mice revealed Mfn2 up-regulation, accompanied by excessive mitochondrial fusion, impaired mitophagy, and astrocyte loss. Elevated MFN2 expression was detected in plasma, postmortem brain tissue, and iPSC-derived astrocytes from patients with MDD. Astrocyte-specific knockdown of Mfn2 restored mitochondrial morphology and mitophagy, thereby preserving astrocyte viability and alleviating depressive-like behaviors. Using mass spectrometry–based label-free proteomics, in vivo calcium imaging, and functional assays, we demonstrated that β-arrestin2 deficiency reduced STAT1 stability, releasing its transcriptional repression on Mfn2 . Normalization of MFN2 expression through astrocytic Mfn2 knockdown or Stat1 overexpression reduced extracellular glutamate accumulation and prevented neuronal hyperexcitability in CSDS mice. Collectively, our findings define astrocytic MFN2-associated astrocyte dysfunction as a central pathological event in depressive behaviors, with the β-arrestin2–STAT1 pathway acting as an upstream regulatory mechanism. This work reveals an astrocytic pathway in depression and highlights a potential therapeutic target that directly addresses astrocyte pathology, beyond the neuron-centered focus of current antidepressant treatments.

Background: Parkinson’s disease (PD) is a global health problem that urgently requires deeper mechanistic insights. Mutations in the ATPase cation transporting 13A2 ( ATP13A2 ) gene are linked to autosomal recessive PD, yet the pathological roles of this gene remain incompletely defined. Previous studies on ATP13A2 have focused mainly on its lysosomal functions in neurons, whereas its role in astrocytes has been largely overlooked. Here, we investigated how ATP13A2 affects astrocytic mitochondrial function and contributes to PD pathology. Results: Using PD mice and Atp13a2 knockout mice, we found that loss of Atp13a2 disrupts mitochondrial morphology and dynamics in the substantia nigra, with astrocytes showing both excessive fission and activation. We further found that Atp13a2 deficiency caused excessive mitochondrial fission, elevated reactive oxygen species (ROS) levels, and promoted extracellular double-stranded DNA release. ELISA measurements revealed significantly increased secretion of IL-1β, IL-6, and TNF-α, indicating increased release of pro-inflammatory cytokines. Importantly, both pharmacological inhibition of fission via Mdivi-1 and Atp13a2 overexpression restored mitochondrial dynamics homeostasis, suppressed oxidative stress, and reduced cytokine secretion. Collectively, these findings demonstrate that ATP13A2 preserves the mitochondrial fission-fusion balance in astrocytes; its loss breaks this balance, thereby triggering neuroinflammation. Conclusion: By uncovering previously unrecognized roles of ATP13A2 in regulating mitochondrial fission and subsequent neuroinflammation, this study provides new insights into PD pathogenesis and identifies potential molecular targets for therapy. These findings open fresh avenues for developing more effective strategies to modify PD progression.

The biochemical composition underlying cytoplasmic residual body (RB) and arrested spermatogonia remains unresolved in spermatogenesis, in part due to limited approaches for intact‐tissue metabolic interrogation. Here we develop Super‐multiplexed Label‐free Raman Imaging (SLRI) to generate 2D/3D biochemical maps of intact Drosophila testes. SLRI delineates major testicular cell types and provides the first in situ, stage‐resolved mapping of cytoplasmic RBs at two discrete phases. We further identify a differentiation‐arrest‐associated metabolic trajectory in spermatogonial clusters, characterized by coordinated spatiotemporal decay of specific biochemical species. Across 42 spatiotemporally variant metabolites and metabolic pathways, SLRI reveals RB‐ and arrest‐enriched signatures. Notably, RBs and arrested spermatogonia display significant biochemical overlap, alongside unique spectral signatures. Furthermore, we uncovered a ring‐like, punctate arrangement of lipids, amino acids, and vitamins encircling RBs, suggesting structured metabolite partitioning during cytoplasmic remodeling. Collectively, SLRI establishes a general framework for high‐dimensional metabolic mapping and remodeling analysis in intact tissues.

Introduction: Environmental factors mediated testicular vacuolization injury is a prevalent occurrence, and its etiology and mitigation strategies have long remained inadequately elucidated. Methods: A testicular injury model was established using Triptolide (TP), with Icariin (ICA) employed as a rescue compound. Function and mechanism investigations primarily employed testicular coefficient and sperm concentration, H&E staining, immunofluorescence staining, and western blot analysis. Single-cell RNA-sequencing (scRNA-seq) predominantly examined the impacts of TP and ICA on various cell populations within the testis at a single-cell resolution. Results: We successfully established a TP-induced model of testicular injury and identified ICA as a protective agent in alleviating testicular vacuolization. Moreover, we delineated a comprehensive single-cell transcriptome profile of ICA in the repair of testicular injury, revealing the pivotal role of Sertoli-germline communications in the genesis of testicular vacuolization and the reparative process mediated by ICA. Furthermore, our investigation unveiled that ICA mitigated TP-induced damage to niche integrity through signatures associated with the blood-testis barrier (BTB), thereby averting substantial germ cell loss via the germline associated-ferroptosis signatures, potentially a key factor in the occurrence of testicular vacuolization injury. Additionally, we also identified ferroptosis-related molecules for testicular vacuolization injury. Discussion: We suggest that TP-induced testicular injury disrupts the spermatogenic microenvironment mediated by the BTB, leading to the formation of testicular vacuoles through the ferroptosis pathway in germ cells. Our findings offer fresh perspectives for ICA on mitigating this process.

Neuroimmune dysregulation is increasingly recognized as a key driver in the pathogenesis of neurodegenerative diseases. In addition to local glial responses within the central nervous system, neuroimmune dysregulation also involves peripheral immune activities and inter-organ communication networks. As previous studies have primarily concentrated on individual peripheral organs or specific immune cell types, the broader systemic immune network remains insufficiently investigated. To delay the onset and progression of neurodegenerative diseases, this review evaluates the latest therapeutic strategies and proposes feasible directions for the rational design of optimal immunomodulatory approaches. By focusing on central nervous system-intrinsic regulatory mechanisms, we delineate how microglia adopt context-dependent phenotypes and further elucidate the dynamic regulatory roles of astrocytes in maintaining blood-brain barrier integrity and synaptic homeostasis. Based on these insights, we propose a feasible direction for achieving a functional balance between neuroprotective phagocytosis and the regulation of chronic neuroinflammation. Furthermore, recent evidence indicates that peripheral immune populations, together with the central nervous system, also play a critical role in the therapeutic regulation of neurodegenerative diseases. As key components of peripheral immune populations, specific T-cell subsets can exert neuroprotective or neurotoxic effects, while B cells and macrophages also make notable contributions through antibody-independent mechanisms and metabolic reprogramming. This review outlines systemic pathways that connect peripheral organs to the brain, demonstrating how gut-derived metabolites, pulmonary immune responses, and renal-hepatic clearance collectively shape the immune regulation of the central nervous system. To achieve cell-specific modulation through neuroimmune pathways, this review further investigates glia-targeted therapeutic strategies, particularly in the areas of small molecules, biologics, and nanocarrier-based platforms. Meanwhile, this review also summarizes the current progress and limitations in neuroimmune-targeted drug development and offers valuable guidance for advancing future drug design. In summary, by integrating the analyses of single cells and multi-omics and utilizing organoid-based modeling, this review highlights the vital transition from broad immunosuppression to precision immunoregulation and proposes a novel regulatory framework spanning from the central to peripheral systems. It further offers targeted and feasible recommendations to advance neuroimmunology from theoretical exploration toward practical therapeutics. However, the implementation of these strategies still faces challenges from the temporal dynamics of immune activation, which could be potentially resolved by the enhancement of human glial cell-based biomimetic models and the improvement of stage-specific biomarkers.

Aims: Parkinson's disease (PD) lacks effective disease‐modifying therapies, despite mitochondrial dysfunction being a key pathogenic factor. This study aimed to identify novel regulators of mitochondrial dynamics and explore their therapeutic relevance. Methods: Transcriptomic analysis was conducted on the substantia nigra (SN) of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mice. SN‐specific lentiviral knockdown or overexpression of nucleoside diphosphate kinase 3 (NME3) was performed in mice. Motor behavior, dopaminergic neuron survival, mitochondrial ultrastructure, and reactive oxygen species (ROS) levels were assessed. Mitochondrial fission was pharmacologically inhibited using the Drp1 inhibitor Mdivi‐1. Results: RNA sequencing revealed a marked reduction of Nme3 in the SN of MPTP‐treated mice. Nme3 knockdown in healthy mice induced PD‐like motor deficits and dopaminergic neurodegeneration, mimicking the MPTP model. Mechanistically, NME3 deficiency disrupted mitochondrial fission‐fusion balance, causing abnormal mitochondrial morphology, excessive ROS production, and neuronal injury. Mdivi‐1 treatment significantly alleviated mitochondrial dysfunction and neurotoxicity. Conversely, SN‐specific Nme3 overexpression in MPTP‐treated mice improved motor performance and preserved dopaminergic neurons by suppressing pathological mitochondrial fission. Conclusion: NME3 is a previously unrecognized regulator of mitochondrial dynamics and a critical contributor to PD pathogenesis. Restoring mitochondrial fission‐fusion balance through genetic or pharmacological approaches provides neuroprotection, highlighting NME3 as a promising target for disease‐modifying PD therapies.

Obstructive sleep apnea‐hypopnea syndrome (OSAHS) is a sleep‐related respiratory disorder that poses a global threat to human health. Chronic intermittent hypoxia (CIH) is its main pathological feature. With the advancements in medical research, the study of CIH‐induced neural injury has gained increasing attention. Studies have shown that CIH can lead to or aggravate neuroinflammation and apoptosis by increasing blood–brain barrier (BBB) permeability, promoting oxidative stress, activating glial cells, and triggering multiple signaling pathways, ultimately resulting in neural injury. These processes contribute to the development of Alzheimer's disease, Parkinson's disease, and stroke. This review aims to summarize the progress in CIH‐induced neural injury and explore various underlying mechanisms, with the goal of providing new insights for the development of therapeutic interventions targeting CIH‐related neural damage.

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons. Accumulating evidence has shown that activation of the NLR family pyrin domain‐containing 3 (NLRP3) inflammasome is an early and cardinal feature in PD progression. Nevertheless, little is known about the effect of NLRP3 in the substantia nigra pars compacta (SNc) on DA neurodegeneration.Methods and results: In the present study, we constructed NLRP3 interference sequences wrapped by lentivirus (LV3‐siNlrp3) to facilitate NLRP3 knockdown in the SNc region by intracerebral stereotactic injection. Then, we explored the effects of NLPR3 knockdown on PD pathologies via behavioral monitoring, immunohistochemistry and western blot analysis in acute 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) mouse model. Moreover, we performed in vitro experiments to investigate the effect of microglial NLRP3 knockdown on DA neuron survival in the context of 1‐methyl‐4‐phenylpyridinium (MPP⁺) stimulation. Our results demonstrated that NLRP3 knockdown in the SNc region significantly improved MPTP‐induced dyskinesia, DA neuronal loss and microglia activation in vivo. Meanwhile, knockdown of microglial NLRP3 attenuated MPP⁺‐induced DA neuronal damage in an indirect coculture system in which neurons were cultured in microglial conditional medium. Cumulatively, these data reveal that microglial NLRP3 located in the SNc region is detrimental to DA neurons survival, and knockdown of microglial NLRP3 is a potential strategy to rescue DA neurons in the progression of PD.Conclusions: This work demonstrates the role of NLRP3 in PD pathogenesis via microglia‐neuron communication, and sheds light on targeting microglial NLRP3 to develop disease‐modifying therapy for PD.

As a late endosomal/lysosomal transport protein of the P5-type, ATP13A2 is capable of removing the abnormal accumulation of α-synuclein, which maintains the homeostasis of metal ions and polyamines in the central nervous system. Furthermore, ATP13A2 regulates the normal function of several organelles such as lysosomes, endoplasmic reticulum (ER) and mitochondria, and maintains the normal physiological activity of neural cells. Especially, ATP13A2 protects dopaminergic (DA) neurons against environmental or genetically induced Parkinson's disease (PD). As we all know, PD is a neurodegenerative disease characterized by the loss of DA neurons in the substantia nigra pars compacta. An increasing number of studies have reported that the loss-of-function of ATP13A2 affects normal physiological processes of various organelles, leading to abnormalities and the death of DA neurons. Previous studies in our laboratory have also shown that ATP13A2 deletion intensifies the neuroinflammatory response induced by astrocytes, thus inducing DA neuronal injury. In addition to elucidating the normal structure and function of ATP13A2, this review summarized the pathological mechanisms of ATP13A2 mutations leading to PD in existing literature studies, deepening the understanding of ATP13A2 in the pathological process of PD and other related neurodegenerative diseases. This review provides inspiration for investigators to explore the essential regulatory role of ATP13A2 in PD in the future.