ACS Chemical Neuroscience最新文献

{"title":"Neurotransmitters in Neural Circuits and Neurological Diseases","authors":"Amir Gholami,&nbsp; and ,&nbsp;Keywan Mortezaee*,&nbsp;","doi":"10.1021/acschemneuro.5c00426","DOIUrl":"10.1021/acschemneuro.5c00426","url":null,"abstract":"<p >Movement and behavioral disturbances occur due to imbalances in neurotransmitter receptor/ligand activities and manifest in the form of basal ganglia- and limbic-related diseases. Diseases in the two systems are all characterized, but there are still complexities and controversies regarding the implication of neural circuits in the pathophysiology of neurological diseases. Thus, we aimed to illustrate the mechanistic backbone of neurotransmitter activities in neural circuits for the sake of better clarification of such diseases and their possible application as a map for the development of new drugs or novel treatment modalities, particularly considering the overlapping circuits for some disorders. The neural circuits unveil hypoactivity of the mesostriatal pathway as a key characteristic of Parkinson’s disease (PD), while disturbances in mesocortical and mesolimbic circuits define schizophrenia pathophysiology. Medium spiny neurons (MSNs) within the striatum take direct and indirect neuronal pathways and express D1 and D2 receptors to finally stimulate the cortical activity. Selective neuronal loss in the striatal indirect pathway defines Huntington’s disease (HD). HD and hemiballismus (HB) display subthalamus nucleus (STN) deactivation and the subsequent removal of the subthalamus stimulatory effect on the pallidum. Attention-deficit hyperactivity disorder (ADHD) evolves due to dysregulations in prefrontal cortex (PFC)-related dopaminergic, norepinephrine (NE), and acetylcholine (Ach) neurons and in the PFC control over amygdala (misery-feeling; low serotonin and imbalanced gamma-aminobutyric acid [GABA]-glutamate [Glu]), with the latter also accountng for increasing fear response in chronic stress and post-traumatic stress disorder (PTSD) and evolving depression phase in bipolar disorder (BD). Defects in the reward-seeking (accumbens) are involved in the BD manic phase.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3653–3664"},"PeriodicalIF":3.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Insights into Dopamine-Mediated Conformational Transitions of Aβ Aggregates in Alzheimer’s Disease","authors":"Sunandini Swain*,&nbsp; and ,&nbsp;Atanu K. Metya*,&nbsp;","doi":"10.1021/acschemneuro.5c00456","DOIUrl":"10.1021/acschemneuro.5c00456","url":null,"abstract":"<p >Alzheimer’s disease (AD) is a looming neurological pandemic that affects over 57 million individuals globally and poses a challenge for the healthcare system due to its complex etiology and the fact that it remains incurable despite extensive research efforts. Among the various pathological contributors, dopaminergic dysfunction has emerged as a critical factor implicated in AD, causing apathy, depression, cognitive decline, and hallucinations, which significantly exacerbate disease progression and patient morbidity. Despite dopamine’s multifarious role in modulating β-amyloid (Aβ) aggregation and in the pathogenesis of AD, the precise molecular interaction mechanism remains poorly understood. In this study, we employ molecular dynamics (MD) simulations to elucidate dopamine’s conformation-specific interactions with Aβ across four hierarchical aggregation states: monomer, trimer, pentamer, and a nine-chain fibrillar assembly. This computational approach reveals that dopamine strongly perturbs the monomeric and trimeric forms, disrupting β-sheet structures and promoting α-helix formation. At the pentameric state, dopamine induces partial α-helix formation while weakening interchain hydrogen bonds and salt bridge interactions, indicating intermediate destabilization. In sharp divergence, the mature fibril exhibits structural rigidity with minimal conformational alteration and no disruption in the β-sheet content. These findings provide an advanced understanding of the conformation-dependent modulation mechanism whereby dopamine selectively interferes with the early nucleation phase rather than fibril elongation; also dopamine exhibits the most pronounced β-sheet disruption in monomers but shows progressively diminished efficacy in higher-order oligomeric and fibrillar assemblies. This selective interaction landscape highlights dopamine’s potential as a modulator of early amyloidogenic events and offers novel insights for understanding dopamine-based therapeutic strategies for AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3774–3789"},"PeriodicalIF":3.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated Lipids in Alzheimer’s Disease: Insights into Biological Pathways through LC–MS/MS Analysis of Human Brain Tissues","authors":"Akeem Sanni,&nbsp;, ,&nbsp;Andrew I. Bennett,&nbsp;, ,&nbsp;Moyinoluwa Adeniyi,&nbsp;, and ,&nbsp;Yehia Mechref*,&nbsp;","doi":"10.1021/acschemneuro.5c00230","DOIUrl":"10.1021/acschemneuro.5c00230","url":null,"abstract":"<p >Alzheimer’s Disease (AD), the leading cause of dementia, is characterized by complex pathological mechanisms that extend beyond amyloid-β plaques and tau tangles. This study investigates the dysregulation of lipids with a focus on phospholipids and sphingolipids, in human post-mortem AD brain tissue using lipidomics methodology. By employing a ZIC-HILIC LC–MS/MS platform, the lipidome of AD (<i>N</i> = 18) was compared to the control (<i>N</i> = 18). Out of 45 quantified lipid classes, 16 belonging to phospholipids and sphingolipids group are differentially expressed (<i>p</i> &lt; 0.05; <i>q</i> &lt; 0.05) in AD compared to control. Key findings include the upregulation of phosphatidylcholine (PC), phosphatidylglycerol (PG), ganglioside GD2 (GD2), phosphatidylinositol (PI), phosphatidylserine (PS), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), and sphingomyelin (phSM), along with the downregulation of ganglioside GD1a in AD. The targeted analysis revealed that ganglioside GD1b exhibits a higher abundance than ganglioside GD1a across all sample groups. System biology analysis revealed that dysregulated lipids impact critical pathways, including glycerophospholipid biosynthesis and sphingolipid metabolism. Additionally, proteomics analysis on the samples showed that proteins such as Amyloid-β precursor protein, pleckstrin homology and SEC7 domain-containing protein 2 (PSD2), and RAC-gamma serine/threonine-protein kinase (AKT) play a role in phospholipid and sphingolipid dysregulation observed in AD. The dysregulated lipids are predicted to be involved in neuronal cell death, necrosis, and apoptosis, advancing our understanding of AD pathogenesis. The study highlights phospholipids and sphingolipids as promising biomarkers and potential therapeutic targets for AD, paving the way for possible diagnostic tools and personalized treatments.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3694–3712"},"PeriodicalIF":3.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Influence of POPC as a Coaggregate in Amyloid-β Oligomer Formation","authors":"Kelsie M. King,&nbsp;, ,&nbsp;Emma M. Cleveland,&nbsp;, ,&nbsp;Allison Pennington,&nbsp;, ,&nbsp;Sarah Fuccello,&nbsp;, and ,&nbsp;Anne M. Brown*,&nbsp;","doi":"10.1021/acschemneuro.5c00605","DOIUrl":"10.1021/acschemneuro.5c00605","url":null,"abstract":"<p >Alzheimer’s Disease (AD) progresses with the formation of neuronal plaques composed primarily of the 42-residue alloform of amyloid-β (Aβ₄₂), whose oligomeric forms induce cytotoxicity by interacting with neuronal membranes, resulting in permeabilization and calcium ion leakage. In AD, elevated phospholipase activity disrupts lipid homeostasis and may increase the concentration of free lipids, such as 1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphocholine (POPC), in extracellular environments proximal to the membrane surface, potentially promoting Aβ₄₂ insertion and toxicity. The coaggregation of Aβ₄₂ with free lipids is believed to modulate mechanisms underlying Aβ₄₂-induced cytotoxicity; however, these interactions are poorly understood. Molecular dynamics (MD) simulations were conducted to investigate Aβ₄₂-POPC interactions and study the aggregation and structural morphologies of hexameric, octameric, and decameric Aβ₄₂ in conjunction with free POPC in a 1:1 ratio. Clustering, radius of gyration, and eccentricity analyses revealed that POPC modulates Aβ₄₂ oligomer morphology in a size-dependent manner. POPC increased compactness and sphericity in octameric and decameric systems, but had minimal or variable effects on hexamers. Hydrophobic interactions between Aβ₄₂ and POPC hydrocarbon tails drove co-oligomerization, and increased hydrophobic solvent accessibility of Aβ₄₂ peptides, altering the energetic profiles of hydrophobic and aromatic residues. To this effect, we hypothesize that Aβ₄₂ coaggregation with POPC may nucleate additional oligomerization events through hydrophobic exposure of Aβ₄₂. This work provides a mechanistic basis for early Aβ₄₂ oligomerization events in lipid microenvironments, offering insights into neurodegenerative pathology.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3886–3898"},"PeriodicalIF":3.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.5c00605","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monitoring of Cerebral ROS and Alleviating Depressive-like Phenotype with a Curcumin-Derived Theranostic Probe","authors":"Liqiang Jin,&nbsp;, ,&nbsp;Yongjian Jiang,&nbsp;, ,&nbsp;Ruina Luo,&nbsp;, ,&nbsp;Xue Tian,&nbsp;, ,&nbsp;Sijin Jiang,&nbsp;, ,&nbsp;Wenjian Zhang,&nbsp;, ,&nbsp;Lu Gan,&nbsp;, ,&nbsp;Jian Yang,&nbsp;, ,&nbsp;Zhaojing Zhu*,&nbsp;, ,&nbsp;Chao Yu*,&nbsp;, and ,&nbsp;Biyue Zhu*,&nbsp;","doi":"10.1021/acschemneuro.5c00355","DOIUrl":"10.1021/acschemneuro.5c00355","url":null,"abstract":"<p >Reactive oxygen species (ROS) play a critical role in the pathogenesis of major depressive disorder (MDD), a global public health challenge with limited effective treatments. However, monitoring and regulating cerebral ROS in living systems remain challenging, limiting both mechanistic studies and treatment strategies. Here, we present CRANAD-61 (Cr-61), a curcumin-derived fluorescent probe, as a multifunctional theranostic agent for the lipopolysaccharide (LPS)-induced depression mouse model. Cr-61 exhibits a ratiometric fluorescence shift (red to green) upon reaction with ROS, enabling detection of ROS levels in the brain. Beyond its detection capabilities, Cr-61 actively scavenges excess ROS, alleviating oxidative stress through suppressing neuroinflammation and improving depressive-like phenotypes. The dual functionality of Cr-61 for ROS detection and therapeutic intervention opens new avenues for advancing the understanding of ROS dynamics as well as providing a novel therapeutic strategy for depression and other ROS-associated diseases.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3745–3757"},"PeriodicalIF":3.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential Region-Specific Neuroprotective Effects of Kynurenine Administration in Healthy Rodents Using High-Resolution Mass Spectrometry","authors":"Sandy Abujrais,&nbsp;, ,&nbsp;Anne Simeit,&nbsp;, ,&nbsp;Mara Link,&nbsp;, ,&nbsp;Fleur Kalberg,&nbsp;, ,&nbsp;Leandrie Pienaar,&nbsp;, ,&nbsp;Radhini Veerappan,&nbsp;, ,&nbsp;Aletta ME Millen,&nbsp;, ,&nbsp;Sooraj Baijnath,&nbsp;, and ,&nbsp;Jonas Bergquist*,&nbsp;","doi":"10.1021/acschemneuro.4c00586","DOIUrl":"10.1021/acschemneuro.4c00586","url":null,"abstract":"<p >The tryptophan (TRP) metabolic pathway produces kynurenine (KYN) and serotonin (5-HT). These are important molecules in the central nervous system, as KYN plays a crucial role in neuroprotection, while 5-HT impacts mood and sleep patterns. The production of KYN is increased in response to inflammatory cytokines and cortisol release, which activates indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), respectively. These enzymes are responsible for converting TRP and KYN into neuroactive molecules including kynurenic acid (KA), quinolinic acid (QA), and 3-hydroxykynurenine (3HK). These metabolites play an important role in neuroprotection and have been linked to the development of several neurological disorders. Therefore, the aim of this study was to investigate the effect of exogenous KYN administration on the activity of the KYN pathway by measuring the brain tissue concentration of these metabolites and the mRNA expression of inflammatory markers, neurotrophic factors, IDO, and TDO. In the acute study, Sprague–Dawley rats (<i>n</i> = 25) received 100 mg/kg kynurenine (0.2 mL, ip) and were terminated at <i>t</i> = 0.5, 1, 2, 3, and 5 h post-KYN administration (<i>n</i> = 5/time point) while in the control group (<i>n</i> = 5) received saline (0.2 mL, ip) and were terminated at <i>t</i> = 1 h. In the chronic study, both KYN and control animals (<i>n</i> = 6 per group) received the same dose as the acute study for 14 days, once daily. Following the treatment period, animals were terminated by decapitation, and trunk blood was collected and separated into plasma, while the brain was surgically removed and dissected into the hippocampus, hypothalamus, midbrain, prefrontal cortex, striatum, cortex, and cerebellum. KYN metabolites were measured by liquid chromatography coupled to high-resolution mass spectrometry, while the mRNA expression of <i>IDO</i>, <i>TDO</i>, brain-derived neurotrophic factor (<i>BDNF</i>), cAMP response element-binding protein (<i>CREB</i>), and interleukin-6 (<i>IL-6</i>) was measured using RT-PCR. KYN and its metabolites were quantified at basal levels in plasma and seven brain regions to assess their distribution in the peripheral and central nervous system. The KA/3HK ratio increased in multiple brain regions, and the plasma KA/QA ratio increased significantly after acute and chronic KYN administration, suggesting peripheral neuroprotection. Reduced plasma and cerebellar KA/3HK ratios suggest region-specific neurotoxicity, whereas the hippocampus accumulates the most KYN and its metabolite KA, suggesting the potential neuroprotective effect of KYN administration in the hippocampus.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3682–3693"},"PeriodicalIF":3.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.4c00586","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbamylation Promotes Sequence-Specific Amyloidogenesis in the α-Synuclein KTKEGV Repeat Motifs","authors":"Joshna Gadhavi,&nbsp;, ,&nbsp;Sumedha Shah,&nbsp;, ,&nbsp;Mohini Patel,&nbsp;, and ,&nbsp;Sharad Gupta*,&nbsp;","doi":"10.1021/acschemneuro.5c00561","DOIUrl":"10.1021/acschemneuro.5c00561","url":null,"abstract":"<p >KTKEGV repeat motifs play a crucial role in regulating the folding of α-synuclein structure and function, including tetramer formation and interaction with membranes. In α-syn, nine KTKEGV imperfect repeats have been reported. Post-translational modifications (PTMs) that could neutralize the positive charge on lysine may disturb the electrostatic interaction of α-syn with the cellular membrane, thereby affecting physiological function. Carbamylation is one such nonenzymatic age-dependent charge-neutralizing PTM which is reported to be elevated in aged people. While some reports have suggested that carbamylation is a proaggregation factor, others have assigned it a protective role. In the present study, we explored the aggregation propensities of KTKEGV repeat motifs and full-length α-syn protein upon carbamylation. We observed distinct aggregation kinetics among various KTKEGV motifs of α-syn, including disease-specific mutated versions, which was confirmed by multiple biophysical techniques such as ThT assay, turbidity measurement, Congo red staining, AFM, and SEM. Notably, the repeat motifs 3 (³²KTKEGVLYV⁴⁰), 5 (⁵⁸KTKEQVTNV⁶⁶), and the core motif (⁷⁷VAQKTV⁸²) exhibited robust fibrillar amyloid formation when carbamylated. Also, repeat motif 4 (⁴³KTKEGVVH⁵⁰), when mutated (E46K, H50Q, and both), becomes an aggregation hotspot, even though the native sequence does not aggregate upon carbamylation. Carbamylation of full-length α-syn protein appears to lead to aggregation with higher fibrillar amyloid content as indicated by a several-fold enhancement of ThT plateau fluorescence. Such carbamylated α-syn aggregates could recruit unmodified α-syn and again led to the formation of well-organized amyloid fibrils. These findings highlight the site-specific role of charge-neutralizing PTMs such as carbamylation α-syn aggregation and provide novel insights into the molecular mechanisms related to synucleinopathies and dementia with Lewy bodies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3861–3872"},"PeriodicalIF":3.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-Penetrating Peptoids: A Dual Functional Strategy for Upcoming Neuroregeneration Application","authors":"Pratikshya Paudel,&nbsp;, ,&nbsp;Rupali Kaur,&nbsp;, and ,&nbsp;Prabir Kumar Gharai*,&nbsp;","doi":"10.1021/acschemneuro.5c00693","DOIUrl":"10.1021/acschemneuro.5c00693","url":null,"abstract":"<p >Effective therapies for neurological conditions are a significant challenge since limited capacity of neurons for regeneration affects neuronal recovery. Despite their ineffective in vivo direct development into neurons, human mesenchymal stem cells (hMSCs) exhibit therapeutic promise through immunological regulation, neuroprotection, and improvement of endogenous repair. A promising strategy is to convert hMSCs into functional neurons using peptoids that also possess cell-penetrating abilities. Therefore, developing cell-penetrating peptoids that combine effective cellular uptake with neural differentiation induction could significantly progress neuroscience research and neuroregenerative treatments.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3631–3633"},"PeriodicalIF":3.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.5c00693","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serotonin 5-HT2C Receptor Signaling Analysis Reveals Psychedelic Biased Agonism","authors":"Emma M. Bonniwell,&nbsp;, ,&nbsp;Rana Alabdali,&nbsp;, ,&nbsp;Joseph J. Hennessey,&nbsp;, ,&nbsp;John L. McKee,&nbsp;, ,&nbsp;Natalie G. Cavalco,&nbsp;, ,&nbsp;Josie C. Lammers,&nbsp;, ,&nbsp;Ethan J. Moore,&nbsp;, ,&nbsp;Luca Franchini,&nbsp;, ,&nbsp;Cesare Orlandi,&nbsp;, and ,&nbsp;John D. McCorvy*,&nbsp;","doi":"10.1021/acschemneuro.5c00647","DOIUrl":"10.1021/acschemneuro.5c00647","url":null,"abstract":"<p >The serotonin 2C receptor (5-HT_2C) is a G protein-coupled receptor implicated in multiple physiological and psychological processes and has been investigated as a therapeutic target for neuropsychiatric conditions such as obesity, drug abuse, and depression. With renewed interest in serotonergic psychedelics for treating depression, 5-HT_2C may contribute to psychedelic-induced therapeutic effects. Despite earlier evidence of 5-HT_2C G protein coupling promiscuity, the full signaling landscape remains incompletely characterized, which may help explain the limited efficacy and potential cancer risks associated with lorcaserin. Here, we provide a comprehensive analysis of 5-HT_2C signaling, confirming and building upon previous findings that the receptor engages Gi/o/z and G12/13 proteins in addition to its primary Gq/11 pathway, and that it preferentially recruits β-arrestin2 over β-arrestin1. We also show that increased RNA editing of the receptor attenuates signaling across all G protein pathways, particularly for G12/13, while preserving β-arrestin recruitment. Profiling of both 5-HT_2C-selective and psychedelic ligands reveals diverse signaling profiles, with serotonergic psychedelics such as LSD and psilocin exhibiting a striking Gq/11 bias due to minimal secondary G protein activation. Altogether, this work provides a foundation for incorporating a broader view of 5-HT_2C signaling modalities into future investigations of 5-HT_2C drug development efforts.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3899–3914"},"PeriodicalIF":3.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycated Alpha-Synuclein Assemblies Cause Distinct Parkinson’s Disease Pathogenesis in Mice","authors":"Akshaya Rajan,&nbsp;, ,&nbsp;Anish Varghese,&nbsp;, ,&nbsp;Shaliya Puthanveedu Hashardeen,&nbsp;, ,&nbsp;Ann Teres Babu,&nbsp;, ,&nbsp;Vinesh Vijayan,&nbsp;, and ,&nbsp;Poonam Thakur*,&nbsp;","doi":"10.1021/acschemneuro.5c00428","DOIUrl":"10.1021/acschemneuro.5c00428","url":null,"abstract":"<p >Alpha-synuclein (α-Syn) misfolding and aggregation are key drivers of Parkinson’s disease (PD) pathology. Mutations and certain post-translational modifications impact its aggregation propensity and pathogenicity. Glycation, a nonenzymatic modification enhanced during hyperglycemia and aging, both known risk factors for PD, has been implicated in α-Syn pathology. Although preformed α-Syn fibrils induce PD-like phenotypes in mice, the impact of glycation on their pathogenicity is unclear. In the current study, we glycated α-Syn using methylglyoxal (MGO), a potent glycating agent, resulting in altered biophysical characteristics in comparison to nonglycated α-Syn. Glycation inhibited the formation of typical β sheet structures under aggregating conditions. Despite that, glycated α-Syn assemblies induced dopaminergic neurodegeneration and neuroinflammation to a similar extent as the nonglycated α-Syn fibrils upon their injection in the mouse substantia nigra (SN). However, these glycated assemblies triggered higher neuroinflammation and increased accumulation of receptor for advanced glycation end products (RAGE) compared to nonglycated fibrils. Consequently, an earlier onset of neuromuscular deficits and anxiety was observed in these mice. Thus, glycation of α-Syn causes distinct PD-associated pathology compared to nonglycated α-Syn, causing an earlier onset of motor symptoms. These findings provide insight into how the glycation of α-Syn due to hyperglycemia may contribute to an increased risk of PD in diabetic populations.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3758–3773"},"PeriodicalIF":3.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}