Patch and matrix striatonigral neurons differentially regulate locomotion.

Striatonigral neurons, known to promote locomotion, reside in both the patch and matrix compartments of the dorsal striatum. However, their compartment-specific contributions to locomotion remain largely unexplored. Using molecular identifier Kremen1 and Calb1 , we showed in mouse models that patch and matrix striatonigral neurons exert opposite influences on locomotion. Matrix striatonigral neurons reduced their activity before the cessation of self-paced locomotion, while patch striatonigral neuronal activity increased, suggesting an inhibitory function. Indeed, optogenetic activation of patch striatonigral neurons suppressed ongoing locomotion with reduced striatal dopamine release, contrasting with the locomotion-promoting effect of matrix striatonigral neurons, which showed an initial increase in dopamine release. Furthermore, genetic deletion of the GABA-B receptor in Aldehyde dehydrogenase 1A1-positive (ALDH1A1 + ) nigrostriatal dopaminergic neurons completely abolished the locomotion-suppressing effect of patch striatonigral neurons. Our findings unravel a compartment-specific mechanism governing locomotion in the dorsal striatum, where patch striatonigral neurons suppress locomotion by inhibiting ALDH1A1 + nigrostriatal dopaminergic neurons.

Progress on early diagnosing Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects both cognition and non-cognition functions. The disease follows a continuum, starting with preclinical stages, progressing to mild cognitive and behavioral impairment, ultimately leading to dementia. Early detection of AD is crucial for better diagnosis and more effective treatment. However, the current AD diagnostic tests of biomarkers using cerebrospinal fluid and/or brain imaging are invasive or expensive, and mostly are still not able to detect early disease state. Consequently, there is an urgent need to develop new diagnostic techniques with higher sensitivity and specificity during the preclinical stages of AD. Various non-cognitive manifestations, including behavioral abnormalities, sleep disturbances, sensory dysfunctions, and physical changes, have been observed in the preclinical AD stage before occurrence of notable cognitive decline. Recent research advances have identified several biofluid biomarkers as early indicators of AD. This review focuses on these non-cognitive changes and newly discovered biomarkers in AD, specifically addressing the preclinical stages of the disease. Furthermore, it is of importance to explore the potential for developing a predictive system or network to forecast disease onset and progression at the early stage of AD.

Halogen doped graphene quantum dots modulate TDP-43 phase separation and aggregation in the nucleus.

TDP-43 is implicated in the dynamic formation of nuclear bodies and stress granules through phase separation. In diseased states, it can further condense into pathological aggregates in the nucleus and cytoplasm, contributing to the onset of amyotrophic lateral sclerosis. In this study, we evaluate the effect of graphene quantum dots (GQDs) with different functional groups on TDP-43's phase separation and aggregation in various cellular locations. We find that halogen atom-doped GQDs (GQDs-Cl, Cl-GQDs-OH) penetrate the nuclear envelope, inhibiting the assembly of TDP-43 nuclear bodies and stress granules under oxidative stress or hyperosmotic environments, and reduce amyloid aggregates and disease-associated phosphorylation of TDP-43. Mechanistic analysis reveals GQDs-Cl and Cl-GQDs-OH modulate TDP-43 phase separation through hydrophobic and electrostatic interactions. Our findings highlight the potential of GQDs-Cl and Cl-GQDs-OH in modulating nuclear protein condensation and pathological aggregation, offering direction for the innovative design of GQDs to modulate protein phase separation and aggregation.

Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures.

α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson's disease and serves as the pathological hallmark of this condition. Different posttranslational modifications have been identified at multiple sites of α-synuclein, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same α-synuclein site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained homogenous α-synuclein monomer with site-specific phosphorylation (pS87) and O-GlcNAcylation (gS87) at S87, respectively. Cryo-EM revealed that pS87 and gS87 α-synuclein form two distinct fibril structures. The GlcNAc situated at S87 establishes interactions with K80 and E61, inducing a unique iron-like fold with the GlcNAc molecule on the iron handle. Phosphorylation at the same site prevents a lengthy C-terminal region including residues 73 to 140 from incorporating into the fibril core due to electrostatic repulsion. Instead, the N-terminal half of the fibril (1-72) takes on an arch-like fibril structure. We further show that both pS87 and gS87 α-synuclein fibrils display reduced neurotoxicity and propagation activity compared with unmodified α-synuclein fibrils. Our findings demonstrate that different posttranslational modifications at the same site can produce distinct fibril structures, which emphasizes link between posttranslational modifications and amyloid fibril formation and pathology.

Association between plasma CTRPs with cognitive impairment and neurodegeneration of Alzheimer's disease.

AIMS: Recent evidence indicated the biological basis of complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) 3, 4, and 14 for affecting brain structure and cognitive function. Thus, we aimed to investigate the association between plasma CTRPs with Alzheimer's disease (AD). METHODS: A multicenter, cross-sectional study recruited patients with AD (n = 137) and cognitively normal (CN) controls (n = 140). After the data collection of demographic characteristics, lifestyle risk factors, and medical history, plasma levels of tau phosphorylated at threonine 217 (pT217), pT181, neurofilament light (NfL), CTRP3, 4, and 14 were examined and compared. Multivariate logistic regression analysis was applied to determine associations of plasma CTPRs with the presence of AD. The correlation analysis was used to explore correlations between plasma CTPRs with scores of Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL) scale, and Clinical Dementia Rating Sum of Boxes (CDR-SB), and levels of plasma pT217, pT181, and NfL. Receiver-operating characteristic (ROC) analysis and Delong's test were used to determine the diagnostic power of plasma CTPRs. RESULTS: Plasma levels of CTRP3, 4, and 14 were higher in AD group than those in CN group. After adjusting for conventional risk factors, CTRP3, CTRP4, and CTRP14 were associated with the presence of AD. In AD patients, CTRP3 was negatively correlated with scores of MMSE and MoCA, while positively correlated with ADL score, CDR-SB score, pT217, and pT181; CTRP4 was positively correlated with CDR-SB score, pT181, and NfL; CTRP14 was negatively correlated with MMSE score, while positively correlated with CDR-SB score, pT217, and NfL. An independent addition of CTRP3 and 4 to the basic model combining age, sex, years of education, APOE4 status, BMI, TG, and HDL-C led to a significant improvement in diagnostic power for AD, respectively. CONCLUSIONS: All the findings preliminarily uncovered associations between plasma CTRPs and AD and suggested the potential of CTRPs as a blood-derived biomarker for AD.

Therapeutic effects of long-term HBOT on Alzheimer's disease neuropathologies and cognitive impairment in APPswe/PS1dE9 mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder with the pathological hallmarks of amyloid beta (Aß) plaques and neurofibrillary tangles (NFTs) in the brain. Although there is a hope that anti-amyloid monoclonal antibodies may emerge as a new therapy for AD, the high cost and side effect is a big concern. Non-drug therapy is attracting more attention and may provide a better resolution for the treatment of AD. Given the fact that hypoxia contributes to the pathogenesis of AD, hyperbaric oxygen therapy (HBOT) may be an effective intervention that can alleviate hypoxia and improve AD. However, it remains unclear whether long-term HBOT intervention in the early stage of AD can slow AD progression and ultimately prevent cognitive impairment in this disease. In this study we applied consecutive 3-month HBOT interventions on 3-month-old APPswe/PS1dE9 AD mice which represent the early stage of AD. When the APPswe/PS1dE9 mice at 9-month-old which represent the disease stage we measured cognitive function, 24-h blood oxygen saturation, Aß and tau pathologies, vascular structure and function, and neuroinflammation in APPswe/PS1dE9 mice. Our results showed that long-term HBOT can attenuate the impairments in cognitive function observed in 9-month-old APPswe/PS1dE9 mice. Most importantly, HBOT effectively reduced the progression of Aß plaques deposition, hyperphosphorylated tau protein aggregation, and neuronal and synaptic degeneration in the AD mice. Further, long-term HBOT was able to enhance blood oxygen saturation level. Besides, long-term HBOT can improve vascular structure and function, and reduce neuroinflammation in AD mice. This study is the first to demonstrate that long-term HBOT intervention in the early stage of AD can attenuate cognitive impairment and AD-like pathologies. Overall, these findings highlight the potential of long-term HBOT as a disease-modifying approach for AD treatment.

α-Synuclein reduces acetylserotonin O-methyltransferase mediated melatonin biosynthesis by microtubule-associated protein 1 light chain 3 beta-related degradation pathway.

Previous studies have demonstrated that α-synuclein (α-SYN) is closely associated with rapid eye movement sleep behavior disorder (RBD) related to several neurodegenerative disorders. However, the exact molecular mechanisms are still rarely investigated. In the present study, we found that in the α-SYNA53T induced RBD-like behavior mouse model, the melatonin level in the plasma and pineal gland were significantly decreased. To elucidate the underlying mechanism of α-SYN-induced melatonin reduction, we investigated the effect of α-SYN in melatonin biosynthesis. Our findings showed that α-SYN reduced the level and activity of melatonin synthesis enzyme acetylserotonin O-methyltransferase (ASMT) in the pineal gland and in the cell cultures. In addition, we found that microtubule-associated protein 1 light chain 3 beta (LC3B) as an important autophagy adapter is involved in the degradation of ASMT. Immunoprecipitation assays revealed that α-SYN increases the binding between LC3B and ASMT, leading to ASMT degradation and a consequent reduction in melatonin biosynthesis. Collectively, our results demonstrate the molecular mechanisms of α-SYN in melatonin biosynthesis, indicating that melatonin is an important molecule involved in the α-SYN-associated RBD-like behaviors, which may provide a potential therapeutic target for RBD of Parkinson's disease.

CircRNA and Stroke: New Insight of Potential Biomarkers and Therapeutic Targets.

Stroke, the second-largest cause of death and the leading cause of disability globally, presents significant challenges in terms of prognosis and treatment. Identifying reliable prognosis biomarkers and treatment targets is crucial to address these challenges. Circular RNA (circRNA) has emerged as a promising research biomarkers and therapeutic targets because of its tissue specificity and conservation. However, the potential role of circRNA in stroke prognosis and treatment remains largely unexplored. This review briefly elucidate the mechanism underlying circRNA's involvement in stroke pathophysiology. Additionally, this review summarizes the impact of circRNA on different forms of strokes, including ischemic stroke and hemorrhagic stroke. And, this article discusses the positive effects of circRNA on promoting cerebrovascular repair and regeneration, maintaining the integrity of the blood-brain barrier (BBB), and reducing neuronal injury and immune inflammatory response. In conclusion, the significance of circRNA as a potential prognostic biomarker and a viable therapeutic target was underscored.

CCL2 promotes metastasis and epithelial-mesenchymal transition of non-small cell lung cancer via PI3K/Akt/mTOR and autophagy pathways.

In non-small cell lung cancer (NSCLC), metastasis is the most common phenotype, and autophagy plays a vital role in its regulation. However, there are limited data on how autophagy-related genes and metastasis-related genes affect NSCLC progression. Our goal was to identify the genes that regulate autophagy and metastasis in NSCLC, and to assess the underlying mechanisms in this current study. RNA sequencing data from public databases were used to screen differentially expressed autophagy- and metastasis-associated genes. Enrichment analyses and immune correlations were conducted to identify hub genes and potential regulating pathways in NSCLC. In this study, we found that CCL2 expression was highly expressed in NSCLC tissues and high CCL2 level was correlated with strong infiltration in lung tissues from NSCLC patients. Overexpression of CCL2 can enhance the metastasis of NSCLC cells in nude mice. Furthermore, CCL2 activated the PI3K/Akt/mTOR signalling pathway axis, promoted epithelial-mesenchymal transition (EMT), and blocked the autophagic flux in NSCLC cells. Therefore, our results indicate that CCL2 promotes metastasis and EMT of NSCLC via PI3K/Akt/mTOR axis and autophagy signalling pathways. We believe that CCL2 could be a probable target for the diagnosis and therapeutics of NSCLC, and this study may expand our understanding of lung cancer.

Circulating proteomic biomarkers for diagnosing sporadic amyotrophic lateral sclerosis: a cross-sectional study.

JOURNAL/nrgr/04.03/01300535-202408000-00039/figure1/v/2023-12-16T180322Z/r/image-tiff Biomarkers are required for the early detection, prognosis prediction, and monitoring of amyotrophic lateral sclerosis, a progressive disease. Proteomics is an unbiased and quantitative method that can be used to detect neurochemical signatures to aid in the identification of candidate biomarkers. In this study, we used a label-free quantitative proteomics approach to screen for substantially differentially regulated proteins in ten patients with sporadic amyotrophic lateral sclerosis compared with five healthy controls. Substantial upregulation of serum proteins related to multiple functional clusters was observed in patients with sporadic amyotrophic lateral sclerosis. Potential biomarkers were selected based on functionality and expression specificity. To validate the proteomics profiles, blood samples from an additional cohort comprising 100 patients with sporadic amyotrophic lateral sclerosis and 100 healthy controls were subjected to enzyme-linked immunosorbent assay. Eight substantially upregulated serum proteins in patients with sporadic amyotrophic lateral sclerosis were selected, of which the cathelicidin-related antimicrobial peptide demonstrated the best discriminative ability between patients with sporadic amyotrophic lateral sclerosis and healthy controls (area under the curve [AUC] = 0.713, P < 0.0001). To further enhance diagnostic accuracy, a multi-protein combined discriminant algorithm was developed incorporating five proteins (hemoglobin beta, cathelicidin-related antimicrobial peptide, talin-1, zyxin, and translationally-controlled tumor protein). The algorithm achieved an AUC of 0.811 and a P-value of < 0.0001, resulting in 79% sensitivity and 71% specificity for the diagnosis of sporadic amyotrophic lateral sclerosis. Subsequently, the ability of candidate biomarkers to discriminate between early-stage amyotrophic lateral sclerosis patients and controls, as well as patients with different disease severities, was examined. A two-protein panel comprising talin-1 and translationally-controlled tumor protein effectively distinguished early-stage amyotrophic lateral sclerosis patients from controls (AUC = 0.766, P < 0.0001). Moreover, the expression of three proteins (FK506 binding protein 1A, cathelicidin-related antimicrobial peptide, and hemoglobin beta-1) was found to increase with disease progression. The proteomic signatures developed in this study may help facilitate early diagnosis and monitor the progression of sporadic amyotrophic lateral sclerosis when used in combination with current clinical-based parameters.

Terahertz Irradiation Improves Cognitive Impairments and Attenuates Alzheimer's Neuropathology in the APPSWE/PS1DE9 Mouse: A Novel Therapeutic Intervention for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the deposition of amyloid-ß (Aß), neurofibrillary tangles, neuroinflammation, and neurodegeneration in the brain. In recent years, considering the unsatisfied benefits of pharmacological therapies, non-pharmacological therapy has become a research hotspot for AD intervention. Terahertz (THz) waves with a range between microwave and infrared regions in the electromagnetic spectrum and high permeability to a wide range of materials have great potential in the bioengineering field. However, its biological impacts on the central nervous system, under either physiological or pathological conditions, are poorly investigated. In this study, we first measured the 0.14 THz waves penetration across the skull of a C57BL/6 mouse and found the percentage of THz penetration to be ~70%, guaranteeing that THz waves can reach the relevant brain regions. We then exposed the APPSWE/PS1DE9 mouse model of AD to repeated low-frequency THz waves on the head. We demonstrated that THz waves treatment significantly improved the cognitive impairment and alleviated AD neuropathology including Aß deposition and tau hyperphosphorylation in the AD mice. Moreover, THz waves treatment effectively attenuated mitochondrial impairment, neuroinflammation, and neuronal loss in the AD mouse brain. Our findings reveal previously unappreciated beneficial effects of THz waves treatment in AD and suggest that THz waves may have the potential to be used as a novel therapeutic intervention for this devastating disease.

Oxygen metabolism abnormality and Alzheimer's disease: An update.

Oxygen metabolism abnormality plays a crucial role in the pathogenesis of Alzheimer's disease (AD) via several mechanisms, including hypoxia, oxidative stress, and mitochondrial dysfunction. Hypoxia condition usually results from living in a high-altitude habitat, cardiovascular and cerebrovascular diseases, and chronic obstructive sleep apnea. Chronic hypoxia has been identified as a significant risk factor for AD, showing an aggravation of various pathological components of AD, such as amyloid ß-protein (Aß) metabolism, tau phosphorylation, mitochondrial dysfunction, and neuroinflammation. It is known that hypoxia and excessive hyperoxia can both result in oxidative stress and mitochondrial dysfunction. Oxidative stress and mitochondrial dysfunction can increase Aß and tau phosphorylation, and Aß and tau proteins can lead to redox imbalance, thus forming a vicious cycle and exacerbating AD pathology. Hyperbaric oxygen therapy (HBOT) is a non-invasive intervention known for its capacity to significantly enhance cerebral oxygenation levels, which can significantly attenuate Aß aggregation, tau phosphorylation, and neuroinflammation. However, further investigation is imperative to determine the optimal oxygen pressure, duration of exposure, and frequency of HBOT sessions. In this review, we explore the prospects of oxygen metabolism in AD, with the aim of enhancing our understanding of the underlying molecular mechanisms in AD. Current research aimed at attenuating abnormalities in oxygen metabolism holds promise for providing novel therapeutic approaches for AD.

The role of Nurr1-miR-30e-5p-NLRP3 axis in inflammation-mediated neurodegeneration: insights from mouse models and patients' studies in Parkinson's disease.

Nuclear receptor related-1 (Nurr1), a ligand-activated transcription factor, is considered a potential susceptibility gene for Parkinson's disease (PD), and has been demonstrated to possess protective effects against inflammation-induced neuronal damage. Despite the evidence showing decreased NURR1 level and increased pro-inflammatory cytokines in cell and animal models as well as in PD patients' peripheral blood mononuclear cells (PBMCs), the underlying mechanism remains elusive. In this study, we investigated the molecular mechanism of Nurr1 in PD-related inflammation. Through the miRNA-sequencing and verification in PBMCs from a cohort of 450 individuals, we identified a significant change of a Nurr1-dependent miRNA miR-30e-5p in PD patients compared to healthy controls (HC). Additionally, PD patients exhibited an elevated plasma interleukin-1ß (IL-1ß) level and increased nucleotide-binding domain-like receptor protein 3 (NLRP3) expression in PBMCs compared to HC. Statistical analyses revealed significant correlations among NURR1, miR-30e-5p, and NLRP3 levels in the PBMCs of PD patients. To further explore the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated PD pathology, we developed a mouse model (Nurr1flox+/Cd11b-cre+, Nurr1cKO) conditionally knocking out Nurr1 in Cd11b-expressing cells. Our investigations in Nurr1cKO mice unveiled significant dopaminergic neurodegeneration following lipopolysaccharide-induced inflammation. Remarkably, Nurr1 deficiency triggered microglial activation and activated NLRP3 inflammasome, resulting in increased IL-1ß secretion. Coincidently, we found that miR-30e-5p level was significantly decreased in the PBMCs and primary microglia of Nurr1cKO mice compared to the controls. Furthermore, our in vitro experiments demonstrated that miR-30e-5p specifically targeted NLRP3. In Nurr1-knockdown microglia, NLRP3 expression was upregulated via miR-30e-5p. In summary, our findings highlight the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated neurodegeneration in PD, the results of which may offer promising prospects for developing PD biomarkers and targeted therapeutic interventions.

A metabolome atlas of mouse brain on the global metabolic signature dynamics following short-term fasting.

Calorie restriction (CR) or a fasting regimen is considered one of the most potent non-pharmacological interventions to prevent chronic metabolic disorders, ameliorate autoimmune diseases, and attenuate aging. Despite efforts, the mechanisms by which CR improves health, particularly brain health, are still not fully understood. Metabolic homeostasis is vital for brain function, and a detailed metabolome atlas of the brain is essential for understanding the networks connecting different brain regions. Herein, we applied gas chromatography-mass spectrometry-based metabolomics and lipidomics, covering 797 structurally annotated metabolites, to investigate the metabolome of seven brain regions in fasted (3, 6, 12, and 24 h) and ad libitum fed mice. Using multivariate and univariate statistical techniques, we generated a metabolome atlas of mouse brain on the global metabolic signature dynamics across multiple brain regions following short-term fasting (STF). Significant metabolic differences across brain regions along with STF-triggered region-dependent metabolic remodeling were identified. We found that STF elicited triacylglycerol degradation and lipolysis to compensate for energy demand under fasting conditions. Besides, changes in amino acid profiles were observed, which may play crucial roles in the regulation of energy metabolism, neurotransmitter signaling, and anti-inflammatory and antioxidant in response to STF. Additionally, this study reported, for the first time, that STF triggers a significant elevation of N-acylethanolamines, a class of neuroprotective lipids, in the brain and liver. These findings provide novel insights into the molecular basis and mechanisms of CR and offer a comprehensive resource for further investigation.

Cell-therapy for Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: Cell-based strategies focusing on replacement or protection of dopaminergic neurons have been considered as a potential approach to treat Parkinson's disease (PD) for decades. However, despite promising preclinical results, clinical trials on cell-therapy for PD reported mixed outcomes and a thorough synthesis of these findings is lacking. We performed a systematic review and meta-analysis to evaluate cell-therapy for PD patients. METHODS: We systematically identified all clinical trials investigating cell- or tissue-based therapies for PD published before July 2023. Out of those, studies reporting transplantation of homogenous cells (containing one cell type) were included in meta-analysis. The mean difference or standardized mean difference in quantitative neurological scale scores before and after cell-therapy was analyzed to evaluate treatment effects. RESULTS: The systematic literature search revealed 106 articles. Eleven studies reporting data from 11 independent trials (210 patients) were eligible for meta-analysis. Disease severity and motor function evaluation indicated beneficial effects of homogenous cell-therapy in the 'off' state at 3-, 6-, 12-, or 24-month follow-ups, and for motor function even after 36 months. Most of the patients were levodopa responders (61.6-100% in different follow-ups). Cell-therapy was also effective in improving the daily living activities in the 'off' state of PD patients. Cells from diverse sources were used and multiple transplantation modes were applied. Autografts did not improve functional outcomes, while allografts exhibited beneficial effects. Encouragingly, both transplantation into basal ganglia and to areas outside the basal ganglia were effective to reduce disease severity. Some trials reported adverse events potentially related to the surgical procedure. One confirmed and four possible cases of graft-induced dyskinesia were reported in two trials included in this meta-analysis. CONCLUSIONS: This meta-analysis provides preliminary evidence for the beneficial effects of homogenous cell-therapy for PD, potentially to the levodopa responders. Allogeneic cells were superior to autologous cells, and the effective transplantation sites are not limited to the basal ganglia. PROSPERO registration number: CRD42022369760.

Linking the cerebellum to Parkinson disease: an update.

Parkinson disease (PD) is characterized by heterogeneous motor and non-motor symptoms, resulting from neurodegeneration involving various parts of the central nervous system. Although PD pathology predominantly involves the nigral-striatal system, growing evidence suggests that pathological changes extend beyond the basal ganglia into other parts of the brain, including the cerebellum. In addition to a primary involvement in motor control, the cerebellum is now known to also have an important role in cognitive, sleep and affective processes. Over the past decade, an accumulating body of research has provided clinical, pathological, neurophysiological, structural and functional neuroimaging findings that clearly establish a link between the cerebellum and PD. This Review presents an overview and update on the involvement of the cerebellum in the clinical features and pathogenesis of PD, which could provide a novel framework for a better understanding the heterogeneity of the disease.

Pathological characteristics of axons and proteome patterns in midbrain dopaminergic neurodegeneration induced by WDR45-deficiency.

Background: Although WD repeats domain 45 (WDR45) mutations have been linked to ß-propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the effects of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. By examining pathological and molecular alterations, we hope to better understand the disease process. Methods: To investigate the effects of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in midbrain DAergic neurons (WDR45cKO). Through a longitudinal study, we assessed alterations in mouse behavior using open field, rotarod, Y-maze, and 3-chamber social approach tests. To examine the pathological changes in DAergic neuron soma and axons, we utilized a combination of immunofluorescence staining and transmission electron microscopy. Additionally, we performed proteomic analyses of the striatum to identify the molecules and processes involved in striatal pathology. Results: Our study of WDR45cKO mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound loss of midbrain DAergic neurons. Prior to neuronal loss, we observed massive axonal enlargements in both the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Additionally, we found that WDR45cKO mice exhibited disrupted autophagic flux. Proteomic analysis of the striatum in these mice showed that many differentially expressed proteins (DEPs) were enriched in amino acid, lipid, and tricarboxylic acid metabolisms. Of note, we observed significant alterations in the expression of genes encoding DEPs that regulate phospholipids catabolic and biosynthetic processes, such as lysophosphatidylcholine acyltransferase 1, ethanolamine-phosphate phospho-lyase, and abhydrolase domain containing 4, N-acyl phospholipase B. These findings suggest a possible link between phospholipid metabolism and striatal axon degeneration. Conclusions: In this study, we have uncovered the molecular mechanisms underlying the contribution of WDR45-deficiency to axonal degeneration, revealing intricate relationships between tubular ER dysfunction, phospholipid metabolism, BPAN and other neurodegenerative diseases. These findings significantly advance our understanding of the fundamental molecular mechanisms driving neurodegeneration and may provide a foundation for developing novel, mechanistically-based therapeutic interventions.

The Crucial Roles of Pitx3 in Midbrain Dopaminergic Neuron Development and Parkinson's Disease-Associated Neurodegeneration.

The degeneration of midbrain dopaminergic (mDA) neurons, particularly in the substantia nigra pars compacta (SNc), is one of the most prominent pathological hallmarks of Parkinson's disease (PD). To uncover the pathogenic mechanisms of mDA neuronal death during PD may provide therapeutic targets to prevent mDA neuronal loss and slow down the disease's progression. Paired-like homeodomain transcription factor 3 (Pitx3) is selectively expressed in the mDA neurons as early as embryonic day 11.5 and plays a critical role in mDA neuron terminal differentiation and subset specification. Moreover, Pitx3-deficient mice exhibit some canonical PD-related features, including the profound loss of SNc mDA neurons, a dramatic decrease in striatal dopamine (DA) levels, and motor abnormalities. However, the precise role of Pitx3 in progressive PD and how this gene contributes to mDA neuronal specification during early stages remains unclear. In this review, we updated the latest findings on Pitx3 by summarizing the crosstalk between Pitx3 and its associated transcription factors in mDA neuron development. We further explored the potential benefits of Pitx3 as a therapeutic target for PD in the future. To better understand the transcriptional network of Pitx3 in mDA neuron development may provide insights into Pitx3-related clinical drug-targeting research and therapeutic approaches.

Chronic Sleep Disturbances Alters Sleep Structure and Tau Phosphorylation in AßPP/PS1 AD Mice and Their Wild-Type Littermates.

BACKGROUND: Emerging evidence indicates that sleep disorders are the common non-cognitive symptoms of Alzheimer's disease (AD), and they may contribute to the pathogenesis of this disease. OBJECTIVE: In this study, we aim to investigate the effect of chronic sleep deprivation (CSD) on AD-related pathologies with a focus on tau phosphorylation and the underlying DNA methylation regulation. METHODS: AßPPswe/PS1ΔE9 AD mice and their wild-type (WT) littermates were subjected to a two-month CSD followed by electroencephalography and electromyography recording. The mice were examined for learning and memory evaluation, then pathological, biochemical, and epigenetic assessments including western blotting, immunofluorescence, dot blotting, and bisulfite sequencing. RESULTS: The results show that CSD caused sleep disturbances shown as sleep pattern change, poor sleep maintenance, and increased sleep fragmentation. CSD increased tau phosphorylation at different sites and increased the level of tau kinases in AD and WT mice. The increased expression of cyclin-dependent kinase 5 (CDK5) may result from decreased DNA methylation of CpG sites in the promoter region of CDK5 gene, which might be associated with the downregulation of DNA methyltransferase 3A and 3B. CONCLUSION: CSD altered AD-related tau phosphorylation through epigenetic modification of tau kinase gene. The findings in this study may give insights into the mechanisms underlying the effects of sleep disturbances on AD pathology and provide new therapeutic targets for the treatment of this disease.