The neuronal ceroid lipofuscinosis family of lysosomal storage diseases, also called CLN1 disease, is characterized by the deficiency of palmitoyl-protein thioesterase 1 (PPT1). In this study, we investigated the impact of PPT1 deficiency on hippocampal GABAergic interneurons (INs) and associated neural network oscillations in a PPT1-KI (CLN1 c.451 C > T (p.R151X)) mouse model. Using a combination of in vivo electrophysiology, immunostaining, and fiber photometry, we observed that PPT1 deficiency led to the activation of caspase 3 in parvalbumin-positive (PV+) INs, an increased activity of pyramidal neurons and theta/gamma oscillation power, and the disruption of theta-gamma cross-frequency coupling (CFC) in the early stage of the CLN1 disease model. In the late stage of the CLN1 disease model, we observed the reduced neuronal activity, extensive neuronal loss including PV+ INs, and the emergence of spontaneous epileptiform discharges and the pathological ripples. Treatment with diazepam partially restored oscillatory coupling and reduced seizure-like activities. Our research indicated that PPT1 deficiency leads to early selective impairment of PV+ INs, triggering overactivation of pyramidal neurons and network dysfunction, which consequently results in seizures and neurodegeneration. This research provides novel insights into the pathogenesis of CLN1 disease and potential therapeutic strategies for the intervention of CLN1 disease by improving the function of inhibitory INs via caspase inhibition.

C-X3-C motif chemokine ligand 1 (CX3CL1), a structurally unique chemokine in the central nervous system (CNS), shapes physiological and pathological processes via specific binding to its receptor, C-X3-C motif chemokine receptor 1 (CX3CR1). Empirical evidence indicates that this signaling axis exerts dual neuroinflammatory effects: It restrains microglial hyperactivation, yet can promote inflammation under conditions such as chronic stress. Notably, it preserves synaptic plasticity and facilitates remyelination. Age-associated reductions in CX3CL1 exhibit a strong correlation with cognitive decline; administration of exogenous CX3CL1 partially mitigates these deficits. This study provides a comprehensive account of the multifaceted functions and regulatory mechanisms of CX3CL1 in CNS diseases, thereby establishing a basis for potential new therapeutic targets.

Patients with Alzheimer's disease (AD) commonly show anxiety behaviors, but the molecular mechanisms are not clear and no efficient intervention exists. Here, we found that overexpression of human wild-type, full-length tau (termed htau) in hippocampus significantly decreased the extracellular γ-aminobutyric acid (GABA) level with inhibition of γ oscillation and the evoked inhibitory postsynaptic potential (eIPSP). With tau accumulation, the mice show age-dependent anxiety behaviors. Among the factors responsible for GABA synthesis, release, uptake, and transport, we found that accumulation of htau selectively suppressed expression of the intracellular vesicular GABA transporter (vGAT). Tau accumulation increased miR92a, which targeted vGAT mRNA 3' UTR and inhibited vGAT translation. Importantly, we found that upregulating GABA tones by intraperitoneal injection of midazolam (a GABA agonist), ChR2-mediated photostimulating and overexpressing vGAT, or blocking miR92a by using specific antagomir or inhibitor efficiently rescued the htau-induced GABAergic dysfunctions with attenuation of anxiety. Finally, we also demonstrated that vGAT level decreased while the miR92a increased in the AD brains. These findings demonstrate that the AD-like tau accumulation induces anxiety through disrupting miR92a-vGAT-GABA signaling, which reveals molecular mechanisms underlying the anxiety behavior in AD patients and potentially leads to the development of new therapeutics for tauopathies.

BACKGROUND:Glioblastoma (GBM), a common type of brain tumor, is currently treatable through radiation therapy. However, there is room for improvement in the effectiveness of treatment. Radiation can lead to an increase in the expression of PD-L1 and VEGF, which might reduce the responsiveness of the tumor to the therapy. This situation underlines the necessity for innovative treatment strategies. OBJECTIVES:In this study, we investigated the potential of attenuated Salmonella carrying the co-expressing plasmid siPD-L1-Endo to effectively inhibit PD-L1 and VEGF expression, thereby enhancing the anti-tumor effects of radiation therapy in GBM-bearing mice. METHODS:The regulatory mechanisms responsible for the treatment effect were detected by Flow cytometry, Immunohistochemistry, TUNEL, Immunofluorescence, H&E staining, and Western blot assays. RESULTS AND DISCUSSION:Upon administration of attenuated Salmonella carrying siRNAPD- L1 and co-expressing endostatin plasmids, the results exhibited significant suppression of tumor growth and tumor cell proliferation, as well as a concurrent decrease in PD-L1 and VEGF expression in tumor tissues. Moreover, the treatment led to reduced expression levels of tumor-related proteins p-Stat3, MMP2, Cyclin D1, and PCNA, an increase in the expression of the apoptosis-related protein cleaved-caspase3, facilitated infiltration of CD4+ and CD8+ T cells within tumor tissues, and an elevation of the ratios of CD4+, CD8+ T cells, and NK cells in the spleen of tumor-bearing mice. CONCLUSION:These findings highlight the ability of attenuated Salmonella carrying siRNA- PD-L1 and co-expressing endostatin plasmids to effectively modulate PD-L1 and VEGF expression, thus strengthening the anti-tumor immune response in GBM-bearing mice subjected to radiation therapy. This combination therapy approach holds promise as a potential avenue for improving the efficacy of radiation therapy in the treatment of glioblastoma.

BackgroundThe Na+/K+-ATPase (NKA), commonly referred to as the sodium pump, is a ubiquitous membrane protein that maintains cellular homeostasis by expelling three sodium ions from the cell and importing two potassium ions using ATP hydrolysis. This enzyme is critical for maintaining resting membrane potential, generating action potentials, and facilitating substance absorption and gland secretion. Additionally, NKA plays a significant role in overall homeostasis and has been implicated in tumor cell regulation.Aim of ReviewThis review aims to provide a comprehensive overview of the post-translational modifications (PTMs) that modulate the function, stability, and intracellular localization of NKA. These PTMs, including phosphorylation, glycosylation, palmitoylation, ubiquitination, and glutathionylation, have emerged as key regulators of NKA activity. By exploring these modifications, we seek to uncover novel insights into the dynamic regulation of NKA and its role in various physiological processes and disease states.Key Scientific Concept of ReviewRecent research has unveiled the intricate interplay between different PTMs of NKA, highlighting their independent and synergistic effects on enzyme function. These modifications not only influence NKA’s ion transport capabilities but also interact with other regulatory pathways, thereby playing a crucial role in health and disease. This review will delve into the specific types of PTMs identified on NKA subunits, their functional consequences, and the potential for these modifications to serve as therapeutic targets. By synthesizing current knowledge and identifying gaps in understanding, this review aims to advance the field and inspire future research directions.

Objectives To profile the mRNA m5C modification landscape in hippocampi from young and aged mice.Methods MeRIP-seq (Methylated RNA Immunoprecipitation Sequencing) technology was conducted to profile m5C-tagged peaks and genes in young and aged hippocampi. M5C methylation-related enzymes were detected using Western blot.Results The numbers of m5C methylation peaks and genes were increased during aging. Among 2010 different m5C peaks, 830 methylated peaks in 782 genes were upregulated and 1,180 methylated peaks in 1,088 genes were downregulated in the aged hippocampi. Most of the m5C sites in the hippocampal transcriptome were distributed at the coding sequence, while the fewest m5C sites found in the 5 ' untranslated regions (5 ' UTRs). Young and aged mice showed a similar enrichment of the most credible motif. The protein level of the m5C demethylase TET2 was downregulated during aging, suggesting that TET2 may potentially influence neuronal health and even cognitive function through epigenetic mechanisms.Conclusions Our data demonstrated different m5C-enriched regions in the young and aged hippocampi, providing novel insight into the possible functions of m5C methylation in brain aging.

Palmitoylation is a reversible lipid modification, regulating protein localization and signaling in neurons. Growth-associated protein 43 (GAP43) requires palmitoylation for axonal development and synaptic plasticity; however, its depalmitoylase and regulation in neural circuits remain unknown. We investigated whether palmitoyl-protein thioesterase 1 (PPT1) is the principal depalmitoylase for GAP43 and examined how disrupted PPT1-GAP43 signaling affects neuronal morphology and circuit function. Using biochemical assays, structural modeling, CRISPR-Cas9-generated GAP43 point mutation mice (GAP43-PM), PPT1-knockout mice (PPT1-KO), electrophysiology, and behavior, we demonstrated that PPT1 interacts with GAP43 at Cys(3) and Cys(4) to mediate its depalmitoylation, disruption of this interaction causes GAP43 hyperpalmitoylation that drove excessive dendritic arborization and aberrant growth cone expansion, enhanced glutamatergic transmission, and hippocampal network hyperexcitability, resulting in cognitive deficits without lysosomal storage pathology. Exogenous PPT1 reduced these morphological/synaptic abnormalities. Our findings establish the PPT1-GAP43 depalmitoylation pathway as essential for neuronal circuit homeostasis; its dysfunction contributes to neurodevelopmental disorders, identifying a potential therapeutic target for palmitoylation-related neurodevelopmental disorders.

INTRODUCTION:Schizophrenia (SCZ) is a severe mental illness characterized by polygenic abnormalities, neural network dysfunction, and cognitive impairment. Mice with reelin gene deficiency (heterozygous reeler mice, HRM) exhibit social withdrawal and dysregulated neurotransmitter systems, including dopamine (DA), similar to abnormalities observed in SCZ patients; therefore, HRM are regarded as a relevant animal model of SCZ. Neural network oscillations in the gamma frequency band (30-100 Hz; γ oscillations) play a crucial role in information processing and neural synchronization in the brain, and disrupted γ oscillations are a hallmark of SCZ. Our previous work showed dysregulated DA modulation of hippocampal γ oscillations in HRM, although the underlying mechanisms remained unclear. In this study, we examined the effects of various DA receptor (DR) agonists and antagonists on hippocampal γ oscillations in wild-type (WT) and HRM to identify mechanisms that may restore DA-dependent modulation of neural network activity in HRM. METHODS:Behavioral performance was assessed using the elevated plus maze (EPM), open field test (OFT), Morris water maze (MWM), and three-chamber social interaction test. Local field potential (LFP) recordings were used to monitor hippocampal CA3 γ oscillations. Western blotting was performed to quantify expression levels of DA receptor subunits. RESULTS:Behavioral tests revealed that HRM displayed reduced social interaction and impaired social novelty preference (three-chamber test), fewer entries and reduced time spent in the open arms (EPM), while maintaining normal motor activity (OFT) and learning and memory abilities (MWM). These findings suggest that HRM exhibit anxiety-like behaviors and deficits in social interaction. LFP recordings showed that the D1R agonist (SKF-81297) and D2R agonist (Quinpirole) increased γ-oscillation power (γ power) in WT mice but had no effect in HRM. The D3R agonist (PD- 128907) did not alter γ power in either genotype. The D4R agonist (PD-168077) caused a modest increase in γ power in HRM. Notably, the D3R antagonist (GR103691) and the D2R antagonist (Phenothiazine), but not the D1R antagonist (SKF-83566) or the D4R antagonist (L-745870), significantly enhanced γ power in HRM. Western blot analysis revealed upregulated D3R expression in the hippocampus of HRM, while D1R, D2R, and D4R levels remained comparable to WT. DISCUSSION:HRM exhibits disrupted dopaminergic modulation of γ oscillations, likely due to impaired D1R/D2R signaling combined with elevated D3R expression. Pharmacological blockade of D3R and, to some extent, D2R effectively restores γ-oscillation modulation in HRM, highlighting the critical role of these receptors in SCZ-related network dysfunction. CONCLUSION:Our findings demonstrate that selective blockade of D2/3 receptors restores DAdependent neuronal network synchronization in HRM. This mechanism may underlie the therapeutic efficacy of D2/3 antagonists in the treatment of schizophrenia.

Background: Transcranial ultrasound stimulation (TUS) has shown promising prospects as a non-invasive neuromodulation technique for both animals and humans. However, ultrasonic propagation characteristics within the brain differ significantly from those in free space. There is currently a lack of comprehensive studies on the effects of skull thickness on focal point position, full width at half maximum (FWHM), and acoustic intensity. Objective: This study investigates the transcranial acoustic field characteristics of 500 kHz focused ultrasound, with a focus on the impact of skull thickness. Methods: The study combined finite element simulations to evaluate the effects of skull thickness on 500 kHz focused ultrasound with experimental investigations across multiple species (mouse, rat, pig, and human). Results: The simulation and experimental results indicate that the skull changes focal length (- 4.4-4.7 mm) and axial focal region (- 7.93-7.59 mm), and the skull causes significant attenuation of acoustic intensity, which increases with skull thickness. The attenuation rate of human skulls is greater than 80 %. We found that the skull thickness has little effect on focal point position (<0.9 mm) and focal region (<1.44 mm) in lateral and vertical directions. Conclusion: Skull thickness has great influence on focal length, axial focal region and acoustic intensity, but has little effect on focal point position and focal region in lateral and vertical directions. And improving axial spatial resolution is a potential method to reduce changes of axial focal region.

This study aims to investigate the mediating role of nutritional status and the inflammatory marker C-reactive protein (CRP) in the relationship between oral frailty and cognitive function in elderly patients with chronic diseases. A cross-sectional design was employed, and From June to December 2024, patients aged ≥ 60 years with chronic diseases from three tertiary hospitals in Henan Province were selected using convenience sampling. Data were collected using questionnaires, including the general information questionnaire, the Oral Frailty Screening Index-8 (OFI-8), the Mini Nutritional Assessment Short Form, the Montreal Cognitive Assessment, and laboratory tests for CRP. Descriptive demographic analysis and Pearson correlation analysis were conducted using SPSS 26.0, and the model 6 in macro program Process 4.1 was employed to test the chain mediation effect. (1) Regression analysis showed that oral frailty had a significant direct impact on cognitive function (β = -0.154, P < 0.01), and nutritional status (β = 0.228, P < 0.001) and CRP (β = -0.200, P < 0.001) also had significant effects on cognitive function. (2) The results of the mediating effect analysis showed that the simple mediating effects of nutritional status and CRP between oral frailty and cognitive function were -0.088 (95

Terahertz radiation at specific frequencies and energies can mediate cellular morphology or function changes by exciting nonlinear resonance effects in proteins or DNA. However, the effects of terahertz radiation on neuronal morphology and function are currently unknown, and the correlation between neuronal morphology and kinetic properties after terahertz radiation remains to be elucidated. In this paper, we first characterized the changes in neuronal morphology by the relative ratio of neuronal cytosol to protruding membrane area. Analyzed the pattern of the influence of terahertz radiation on neuronal morphology and the cumulative effect. On this basis, this paper constructs a kinetic model of neurons regulated by terahertz radiation, investigates the influence law of terahertz radiation on the kinetic properties of neurons, and analyzes the correlation between neuronal morphology and kinetic properties. The results showed that terahertz radiation caused a decrease in the membrane area ratio of neuronal cytosol to protrusion, and this effect started on the first day of terahertz radiation and lasted until the end of terahertz radiation; terahertz radiation changed the neuronal discharge pattern by decreasing the membrane area ratio of neuronal cytosol to protrusion and lowered the frequency of neuronal inter-cluster discharges and amplitude of action potentials, and increased the neuronal intra-cluster discharge. In addition, terahertz radiation can increase the peak value of neuronal postsynaptic currents by decreasing the membrane area ratio. In summary, terahertz radiation can modulate neurons' morphology and change their firing patterns and kinetic properties by affecting their morphology. These predict that terahertz radiation at specific frequencies and energies can be developed as a novel, molecular-level neuromodulation technique for intervening or treating neuronal degenerative diseases.

Numb is an evolutionarily conserved protein that regulates the differentiation of neuronal progenitor cells through unknown mechanisms. Numb has four alternative splice variants with different lengths of phosphotyrosine-binding (PTB) and proline-rich regions (PRR) domains. In this study, we demonstrated that Numb expression was increased in the primary cultures of rat cortical and hippocampal neurons over time in vitro, and Numb antisense inhibited neurite outgrowth. We verified that cells overexpressing short PTB (SPTB) or long PTB (LPTB) domains exhibited differentiation or proliferation, respectively. SPTB-mediated differentiation was related to the PRR domains, as cells expressing SPTB/LPRR had longer dendrites and more branched dendrites than cells expressing SPTB/SPRR. The differentiation of both cell types was completely blocked by the Ca2+ chelator. Western blot analysis revealed the increased total protein expression of voltage-gated calcium channel (VGCC) subunit α1C and α1D in cells expressing SPTB and LPTB Numb. The increased expression of the VGCC β3 subunit was only observed in cells expressing SPTB Numb. Immunocytochemistry further showed that SPTB-mediated cell differentiation was associated with increased membrane expression of VGCC subunits α1C, α1D and β3, which corresponded to the higher Ca2+ current (ICa) densities. Furthermore, we found that VGCC of cells transfected with SPTB/SPRR or SPTB/LPRR Numb isoforms exhibit steady-state inactivation (SSI) in both differentiated and undifferentiated phenotypes. A similar SSI of VGCC was observed in the differentiated cells transfected with SPTB/SPRR or SPTB/LPRR Numb isoforms, whereas a left shift SSI of VGCC in cells expressing SPTB/LPRR was detected in the undifferentiated cells. Collectively, these data indicate that SPTB domain is essential for neurite outgrowth involving in membrane expression of VGCC subunits, and LPRR plays a role in neuronal branching and the regulation of VGCC inactivation kinetics.

Abstract Objectives To investigate the correlation between serum angiopoietin‐like protein 4 (ANGPTL4) levels, white matter hyperintensity (WMH), and cognitive impairment (CI) in patients with cerebral small vessel disease (CSVD). Methods This cross‐sectional study enrolled 171 patients with CSVD who attended the First Affiliated Hospital of Xinxiang Medical University from December 2021 to July 2022. All subjects underwent a 3.0T head magnetic resonance imaging, neuropsychology assessment, and blood sampling. Serum ANGPTL4 levels were detected by enzyme‐linked immunosorbent assay and the severity of WMH was assessed by the Fazekas scale. According to the Montreal Cognitive Assessment (MoCA) scale, subjects were divided into normal cognition group (NC, n = 80) and CI group (n = 91). According to the total Fazekas scores, subjects were divided into a mild WMH group (n = 84), a moderate WMH group (n = 70), and a severe WMH group (n = 17). Results Serum ANGPTL4 levels were significantly higher in the CI group than in the NC group (p < .05) and were negatively correlated with mini–mental state examination scores and MoCA scores (r = −0.26, −0.341, p < .05). Serum ANGPTL4 levels increased significantly in the mild to moderate WMH group but tended to decrease in the severe WMH group. Binary logistic regression analysis showed that ANGPTL4 was an independent influencing factor for CSVD‐CI (OR = 2.062, 95% CI (1.591–2.674), p < .001). The area under curve of ANGPTL4 for CSVD‐CI was 0.847 (0.791–0.903). Conclusion ANGPTL4 may be involved in the process of white matter damage and CI in CSVD patients and shows a diagnostic value for CSVD‐CI.

Aging-related decline in memory and synaptic function are associated with the dysregulation of calcium homeostasis, attributed to the overexpression of voltage-gated calcium channels (VGCC). The membrane insertion of AMPAR governed by the AMPAR auxiliary proteins is essential for synaptic transmission and plasticity (LTP). In this study, we demonstrated the hippocampal expression of the transmembrane AMPAR regulatory proteins γ-8 (TARPγ8) was reduced in aged mice along with the reduced CaMKIIα activity and memory impairment. We further showed that TARPγ8 expression was dependent on CaMKIIα activity. Inhibition of CaMKIIα activity significantly reduced the hippocampal TARPγ8 expression and CA3-CA1 LTP in young mice to a similar level to that of the aged mice. Furthermore, the knockdown of hippocampal TARPγ8 impaired LTP and memory in young mice, which mimicked the aging-related changes. We confirmed the enhanced hippocampal VGCC (Cav-1.3) expression in aged mice and found that inhibition of VGCC activity largely increased both p-CaMKIIα and TARPγ8 expression in aged mice, whereas inhibition of NMDAR or Calpains had no effect. In addition, we found that the exogenous expression of human TARPγ8 in the hippocampus in aged mice restored LTP and memory function. Collectively, these results indicate that the synaptic and cognitive impairment in aging is associated with the downregulation of CaMKIIα-TARPγ8 signaling caused by VGCC activation. Our results suggest that TARPγ8 may be a key molecular biomarker for brain aging and that boosting CaMKIIα-TARPγ8 signaling may be critical for the restoration of synaptic plasticity of aging and aging-related diseases.

The downregulation of Cadm4 (Cell adhesion molecular 4) is a prominent feature in demyelination diseases, yet, the underlying molecular mechanism remains elusive. Here, we reveal that Cadm4 undergoes specific palmitoylation at cysteine-347 (C347), which is crucial for its stable localization on the plasma membrane (PM). Mutation of C347 to alanine (C347A), blocking palmitoylation, causes Cadm4 internalization from the PM and subsequent degradation. In vivo experiments introducing the C347A mutation (Cadm4-KI) lead to severe myelin abnormalities in the central nervous system (CNS), characterized by loss, demyelination, and hypermyelination. We further identify ZDHHC3 (Zinc finger DHHC-type palmitoyltransferase 3) as the enzyme responsible for catalyzing Cadm4 palmitoylation. Depletion of ZDHHC3 reduces Cadm4 palmitoylation and diminishes its PM localization. Remarkably, genetic deletion of ZDHHC3 results in decreased Cadm4 palmitoylation and defects in CNS myelination, phenocopying the Cadm4-KI mouse model. Consequently, altered Cadm4 palmitoylation impairs neuronal transmission and cognitive behaviors in both Cadm4-KI and ZDHHC3 knockout mice. Importantly, attenuated ZDHHC3-Cadm4 signaling significantly influences neuroinflammation in diverse demyelination diseases. Mechanistically, we demonstrate the predominant expression of Cadm4 in the oligodendrocyte lineage and its potential role in modulating cell differentiation via the WNT-β-Catenin pathway. Together, our findings propose that dysregulated ZDHHC3-Cadm4 signaling contributes to myelin abnormalities, suggesting a common pathological mechanism underlying demyelination diseases associated with neuroinflammation.

Rationale: Tripeptidyl peptidase II (TPP2) has been proven to be related to human immune and neurological diseases. It is generally considered as a cytosolic protein which forms the largest known protease complex in eukaryotic cells to operate mostly downstream of proteasomes for degradation of longer peptides. However, this canonical function of TPP2 cannot explain its role in a wide variety of biological and pathogenic processes. The mechanistic interrelationships and hierarchical order of these processes have yet to be clarified. Methods: Animals, cells, plasmids, and viruses established and/or used in this study include: TPP2 knockout mouse line, TPP2 conditional knockout mouse lines (different neural cell type oriented), TRE-TPP2 knockin mouse line on the C57BL/6 background; 293T cells with depletion of TPP2, ATF6, IRE1, PERK, SYVN1, UCHL1, ATG5, CEPT1, or CCTα, respectively; 293T cells stably expressing TPP2, TPP2 S449A, TPP2 S449T, or CCTα-KDEL proteins on the TPP2-depleted background; Plasmids for eukaryotic transient expression of rat CYP19A1-Flag, CYP19A1 S118A-Flag, CYP19A1 S118D-Flag, Sac I ML GFP Strand 11 Long, OMMGFP 1-10, G-CEPIA1er, GCAMP2, CEPIA3mt, ACC-GFP, or SERCA1-GFP; AAV2 carrying the expression cassette of mouse CYP19A1-3 X Flag-T2A-ZsGreen. Techniques used in this study include: Flow cytometry, Immunofluorescence (IF) staining, Immunohistochemical (IHC) staining, Luxol fast blue (LFB) staining, β-galactosidase staining, Lipid droplet (LD) staining, Calcium (Ca2+) staining, Stimulated emission depletion (STED) imaging, Transmission electron microscopic imaging, Two-photon imaging, Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end Labeling (TUNEL) assay, Bromodeoxyuridine (BrdU) assay, Enzymatic activity assay, Proximity ligation assay (PLA), In vivo electrophysiological recording, Long-term potentiation (LTP) recording, Split-GFP-based mitochondria-associated membrane (MAM) detection, Immunoprecipitation (IP), Cellular fractionation, In situ hybridization, Semi-quantitative RT-PCR, Immunoblot, Mass spectrometry-based lipidomics, metabolomics, proteomics, Primary hippocampal neuron culture and Morris water maze (MWM) test. Results: We found that TPP2, independent of its enzymatic activity, plays a crucial role in maintaining the homeostasis of intracellular Ca2+ and phosphatidylcholine (PC) in the central nervous system (CNS) of mice. In consistence with the critical importance of Ca2+ and PC in the CNS, TPP2 gene ablation causes presenile dementia in female mice, which is closely associated with Ca2+/PC dysregulation-induced endoplasmic reticulum (ER) stress, abnormal autophagic degradation of CYP19A1 (aromatase), and estrogen depletion. This work therefore uncovers a new role of TPP2 in lipogenesis and neurosteroidogenesis which is tightly related to cognitive function of adult female mice. Conclusion: Our study reveals a crucial role of TPP2 in controlling homeostasis of Ca2+ and lipids in CNS, and its deficiency causes sexual dimorphism in dementia. Thus, this study is not only of great significance for elucidating the pathogenesis of dementia and its futural treatment, but also for interpreting the role of TPP2 in other systems and their related disorders.

Vacuole membrane protein 1 (VMP1) is an integral membrane protein that plays a pivotal role in cellular processes, particularly in the regulation of autophagy. Autophagy, a self-degradative mechanism, is essential for maintaining cellular homeostasis by degradation and recycling damaged organelles and proteins. VMP1 involved in the autophagic processes include the formation of autophagosomes and the subsequent fusion with lysosomes. Moreover, VMP1 modulates endoplasmic reticulum (ER) calcium levels, which is significant for various cellular functions, including protein folding and cellular signaling. Recent studies have also linked VMP1 to the cellular response against viral infections and lipid droplet (LD). Dysregulation of VMP1 has been observed in several pathological conditions, including neurodegenerative diseases such as Parkinson’s disease (PD), pancreatitis, hepatitis, and tumorogenesis, underscoring its potential as a therapeutic target. This review aims to provide an overview of VMP1’s multifaceted roles and its implications in disease pathology.

The infantile neuronal ceroid lipofuscinosis, also called CLN1 disease, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). Identifying the depalmitoylation substrates of PPT1 is crucial for understanding CLN1 disease. In this study, we found that GABAAR, the critical synaptic protein essential for inhibitory neurotransmission, is a substrate of PPT1. PPT1 depalmitoylates GABAAR α1 subunit at Cystein-260, while binding to Cystein-165 and -179. Mutations of PPT1 or its GABAAR α1 subunit binding site enhanced inhibitory synaptic transmission and strengthened oscillations powers but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient and Gabra1em1 mice. Our study highlights the critical role of PPT1 in maintaining GABAAR palmitoylation homeostasis and reveals a previously unknown molecular pathway in CLN1 diseases induced by PPT1 mutations.

Summary CLN1 disease, also called infantile neuronal ceroid lipofuscinosis, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). To identify depalmitoylation substrate of PPT1 is crucial to understand CLN1 disease. In this study, we found that PPT1 depalmitoylates GABA A R α1 subunit at Cystein-260, while binding to Cystein-165 and −179. Mutations of PPT1 or its GABA A R α1 subunit binding site result in enhanced inhibitory synaptic transmission, strengthened and oscillation but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient and Gabra1 em1 mice. Our study highlights the critical role of PPT1 in maintaining GABA A R palmitoylation homeostasis and reveals a previously unknown molecular pathway in PPT1 induced diseases.