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Cross-Interaction with Amyloid-β Drives Pathogenic Structural Transformation within the Amyloidogenic Core Region of TDP-43.
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-04-01 DOI: 10.1021/acschemneuro.5c00084
Adam J Gatch, Feng Ding

Alzheimer's disease (AD) is the world's most prevalent neurodegenerative disorder, characterized neuropathologically by senile plaques and neurofibrillary tangles formed by amyloid-β (Aβ) and tau, respectively. Notably, a subset of AD patients also exhibits pathological aggregates composed of TAR DNA-Binding Protein 43 (TDP-43). Clinically, the presence of TDP-43 copathology in AD correlates with more severe cognitive decline and faster disease progression. While previous studies have shown that TDP-43 can exacerbate Aβ toxicity and modulate its assembly dynamics by delaying fibrillization and promoting oligomer formation, the impact of the Aβ interaction on the structural dynamics and aggregation of TDP-43 remains unclear. Here, we employed all-atom discrete molecular dynamics simulations to study the direct interaction between Aβ42, the more amyloidogenic isoform of Aβ, and the amyloidogenic core region (ACR) of TDP-43, which spans residues 311-360 and is critical for TDP-43 aggregation. We found that monomeric Aβ42 could strongly bind to the ACR, establishing sustained contact through intermolecular hydrogen bonding. In contrast, simulation of ACR dimerization revealed a transient helix-helix interaction, experimentally known to drive the phase separation behavior of TDP-43. The binding of the ACR to an Aβ42 fibril seed resulted in significant structural transformation, with the complete unfolding of the helical region being observed. Furthermore, interaction with the Aβ42 fibril seed catalyzed the formation of a parallel, in-register intermolecular β-sheet between two ACR monomers. Collectively, our computational study provides important theoretical insights into TDP-43 pathology in AD, demonstrating that Aβ42, especially in its fibrillar form, may catalyze the pathogenic structural transformation within the TDP-43 ACR that initiates its aberrant aggregation.

{"title":"Cross-Interaction with Amyloid-β Drives Pathogenic Structural Transformation within the Amyloidogenic Core Region of TDP-43.","authors":"Adam J Gatch, Feng Ding","doi":"10.1021/acschemneuro.5c00084","DOIUrl":"10.1021/acschemneuro.5c00084","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the world's most prevalent neurodegenerative disorder, characterized neuropathologically by senile plaques and neurofibrillary tangles formed by amyloid-β (Aβ) and tau, respectively. Notably, a subset of AD patients also exhibits pathological aggregates composed of TAR DNA-Binding Protein 43 (TDP-43). Clinically, the presence of TDP-43 copathology in AD correlates with more severe cognitive decline and faster disease progression. While previous studies have shown that TDP-43 can exacerbate Aβ toxicity and modulate its assembly dynamics by delaying fibrillization and promoting oligomer formation, the impact of the Aβ interaction on the structural dynamics and aggregation of TDP-43 remains unclear. Here, we employed all-atom discrete molecular dynamics simulations to study the direct interaction between Aβ42, the more amyloidogenic isoform of Aβ, and the amyloidogenic core region (ACR) of TDP-43, which spans residues 311-360 and is critical for TDP-43 aggregation. We found that monomeric Aβ42 could strongly bind to the ACR, establishing sustained contact through intermolecular hydrogen bonding. In contrast, simulation of ACR dimerization revealed a transient helix-helix interaction, experimentally known to drive the phase separation behavior of TDP-43. The binding of the ACR to an Aβ42 fibril seed resulted in significant structural transformation, with the complete unfolding of the helical region being observed. Furthermore, interaction with the Aβ42 fibril seed catalyzed the formation of a parallel, in-register intermolecular β-sheet between two ACR monomers. Collectively, our computational study provides important theoretical insights into TDP-43 pathology in AD, demonstrating that Aβ42, especially in its fibrillar form, may catalyze the pathogenic structural transformation within the TDP-43 ACR that initiates its aberrant aggregation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750247","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}
引用次数: 0
Biophysical Characterization and Preformulation Studies of Human Mesencephalic Astrocyte-Derived Neurotropic Factor.
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-04-01 DOI: 10.1021/acschemneuro.4c00560
Robert W Payne, Tiansheng Li, Albert Li, Cynthia Li, Ryan R Manning, Glenn A Wilson, Charles S Henry, Mark Cornell Manning

A novel neurotrophic factor, human mesencephalic astrocyte-derived neurotrophic factor (hMANF), is being considered a therapeutic agent for a variety of diseases. However, little, if anything, has been reported about its stability. A preformulation study was conducted to assess the stability of hMANF as a function of pH and temperature. In addition, the effects of buffers and other excipients were evaluated as well. While the chemical and physical stability of hMANF decreases near pH 4, overall, the protein appears to be quite stable, especially near pH 6. Both histidine and phosphate appear to be suitable buffers in this pH range. Some loss of stability was noted above pH 6.5 as well. The stability profile of hMANF was comparable at 1 and 10 mg/mL. The decreased stability at acidic pH is correlated with the loss of the native α-helical conformation, as shown by FTIR spectroscopy. These studies indicate that hMANF is quite stable near pH 6, and formulations capable of exhibiting adequate long-term stability in aqueous solutions should be possible.

{"title":"Biophysical Characterization and Preformulation Studies of Human Mesencephalic Astrocyte-Derived Neurotropic Factor.","authors":"Robert W Payne, Tiansheng Li, Albert Li, Cynthia Li, Ryan R Manning, Glenn A Wilson, Charles S Henry, Mark Cornell Manning","doi":"10.1021/acschemneuro.4c00560","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00560","url":null,"abstract":"<p><p>A novel neurotrophic factor, human mesencephalic astrocyte-derived neurotrophic factor (hMANF), is being considered a therapeutic agent for a variety of diseases. However, little, if anything, has been reported about its stability. A preformulation study was conducted to assess the stability of hMANF as a function of pH and temperature. In addition, the effects of buffers and other excipients were evaluated as well. While the chemical and physical stability of hMANF decreases near pH 4, overall, the protein appears to be quite stable, especially near pH 6. Both histidine and phosphate appear to be suitable buffers in this pH range. Some loss of stability was noted above pH 6.5 as well. The stability profile of hMANF was comparable at 1 and 10 mg/mL. The decreased stability at acidic pH is correlated with the loss of the native α-helical conformation, as shown by FTIR spectroscopy. These studies indicate that hMANF is quite stable near pH 6, and formulations capable of exhibiting adequate long-term stability in aqueous solutions should be possible.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762603","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}
引用次数: 0
Caffeine and Nicotine with N-Substituted Diazirine Photoaffinity Labels Form Adducts at Tyrosine-39 of α-Synuclein.
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-04-01 DOI: 10.1021/acschemneuro.5c00074
Melissa Mejia-Gutierrez, Brigitte Moser, Marissa Pirlot, Haixia Zhang, Paulos Chumala, George S Katselis, David R J Palmer, Ed S Krol

Aggregates of the protein α-synuclein are found in Lewy bodies in the brains of Parkinson's disease (PD) patients. Small molecules that can attenuate or halt α-synuclein aggregation have been studied as potential therapeutics for PD. However, we have a limited understanding of how these molecules bind to α-synuclein. We previously identified that caffeine, nicotine, and 1-aminoindan all bind to both the N- and C-terminus of α-synuclein, although the binding location remains unknown. In an effort to identify these binding regions on α-synuclein, we synthesized diazirine photoaffinity probes attached to caffeine (C-Dz), nicotine (N-Dz), and 1-aminoindan (I-Dz) and allowed each to react with α-synuclein in vitro. We then treated the incubation mixture with trypsin and employed time-of-flight mass spectrometry to analyze the resulting peptides. Our findings reveal a distinctive binding pattern among the probes: C-Dz forms covalent bonds with Tyr-39 and Glu-20, while N-Dz selectively forms a covalent bond with Tyr-39. Intriguingly, we could not detect the labeling of I-Dz to any specific amino acids. All of the diazirine-bound peptides were found near the N-terminus. Our results suggest that the N-terminal region near Tyr-39 bears further study to elucidate the binding interactions of small molecules with α-synuclein and may be a target for anti-PD agents.

{"title":"Caffeine and Nicotine with N-Substituted Diazirine Photoaffinity Labels Form Adducts at Tyrosine-39 of α-Synuclein.","authors":"Melissa Mejia-Gutierrez, Brigitte Moser, Marissa Pirlot, Haixia Zhang, Paulos Chumala, George S Katselis, David R J Palmer, Ed S Krol","doi":"10.1021/acschemneuro.5c00074","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00074","url":null,"abstract":"<p><p>Aggregates of the protein α-synuclein are found in Lewy bodies in the brains of Parkinson's disease (PD) patients. Small molecules that can attenuate or halt α-synuclein aggregation have been studied as potential therapeutics for PD. However, we have a limited understanding of how these molecules bind to α-synuclein. We previously identified that caffeine, nicotine, and 1-aminoindan all bind to both the N- and C-terminus of α-synuclein, although the binding location remains unknown. In an effort to identify these binding regions on α-synuclein, we synthesized diazirine photoaffinity probes attached to caffeine (C-Dz), nicotine (N-Dz), and 1-aminoindan (I-Dz) and allowed each to react with α-synuclein <i>in vitro</i>. We then treated the incubation mixture with trypsin and employed time-of-flight mass spectrometry to analyze the resulting peptides. Our findings reveal a distinctive binding pattern among the probes: C-Dz forms covalent bonds with Tyr-39 and Glu-20, while N-Dz selectively forms a covalent bond with Tyr-39. Intriguingly, we could not detect the labeling of I-Dz to any specific amino acids. All of the diazirine-bound peptides were found near the N-terminus. Our results suggest that the N-terminal region near Tyr-39 bears further study to elucidate the binding interactions of small molecules with α-synuclein and may be a target for anti-PD agents.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762609","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}
引用次数: 0
Calycosin Inhibit PANoptosis and Alleviate Brain Damage: A Bioinformatics and Experimental Verification Approach.
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-03-29 DOI: 10.1021/acschemneuro.5c00072
Huiyan An, Chongyu Shao, Yu He, Huifen Zhou, Ting Wang, Guanfeng Xu, Jiehong Yang, Haitong Wan

PANoptosis is a newly identified form of cell death that encompasses pyroptosis, apoptosis, and necroptosis. Numerous studies have highlighted the significance of PANoptosis in brain ischemia-reperfusion (I/R) injury. Calycosin, a natural product with diverse biological activities, has demonstrated a significant reduction in neuronal death caused by ischemic brain injury by modulating multiple cell death pathways. In order to investigate the potential mechanisms underlying the neuroprotective role of calycosin in alleviating PANoptosis-induced damage in ischemic stroke therapy, we used mouse hippocampal neuronal cell line HT22 to stimulate ischemia in vitro through Oxygen and Glucose Deprivation/Reperfusion (OGD/R) and established molecular docking to assess the binding affinity of Calycosin with key targets and molecular dynamics simulations (MDS) to study the stability of the ligand-protein complex. The results demonstrate that Calycosin could improve the cell growth of HT22, leading to enhanced cell viability, reduced lactate dehydrogenase leakage, and decreased cell apoptosis after OGD/R. It also regulated the expression of PANoptosis-related genes such as NLRP3, GSDMD, MLKL, and RIPK1 and increased the Bcl-2/Bax ratio, effectively reducing cellular damage and providing protection. Molecular docking and MDS simulations demonstrated strong binding activity and stability between Calycosin and PANoptosis-related targets. Furthermore, Calycosin successfully passed the drug similarity (DS) evaluation and exhibited favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and biological activity. In conclusion, Calycosin could alleviate ischemic stroke by inhibiting PANoptosis, reducing neuronal inflammation and apoptosis, and improving damage caused by the OGD/R. Thus, it could serve as a potential therapy for ischemic stroke.

{"title":"Calycosin Inhibit PANoptosis and Alleviate Brain Damage: A Bioinformatics and Experimental Verification Approach.","authors":"Huiyan An, Chongyu Shao, Yu He, Huifen Zhou, Ting Wang, Guanfeng Xu, Jiehong Yang, Haitong Wan","doi":"10.1021/acschemneuro.5c00072","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00072","url":null,"abstract":"<p><p>PANoptosis is a newly identified form of cell death that encompasses pyroptosis, apoptosis, and necroptosis. Numerous studies have highlighted the significance of PANoptosis in brain ischemia-reperfusion (I/R) injury. Calycosin, a natural product with diverse biological activities, has demonstrated a significant reduction in neuronal death caused by ischemic brain injury by modulating multiple cell death pathways. In order to investigate the potential mechanisms underlying the neuroprotective role of calycosin in alleviating PANoptosis-induced damage in ischemic stroke therapy, we used mouse hippocampal neuronal cell line HT22 to stimulate ischemia in vitro through Oxygen and Glucose Deprivation/Reperfusion (OGD/R) and established molecular docking to assess the binding affinity of Calycosin with key targets and molecular dynamics simulations (MDS) to study the stability of the ligand-protein complex. The results demonstrate that Calycosin could improve the cell growth of HT22, leading to enhanced cell viability, reduced lactate dehydrogenase leakage, and decreased cell apoptosis after OGD/R. It also regulated the expression of PANoptosis-related genes such as NLRP3, GSDMD, MLKL, and RIPK1 and increased the Bcl-2/Bax ratio, effectively reducing cellular damage and providing protection. Molecular docking and MDS simulations demonstrated strong binding activity and stability between Calycosin and PANoptosis-related targets. Furthermore, Calycosin successfully passed the drug similarity (DS) evaluation and exhibited favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and biological activity. In conclusion, Calycosin could alleviate ischemic stroke by inhibiting PANoptosis, reducing neuronal inflammation and apoptosis, and improving damage caused by the OGD/R. Thus, it could serve as a potential therapy for ischemic stroke.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741717","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}
引用次数: 0
Toward a Small-Molecule Antagonist Radioligand for Positron Emission Tomography Imaging of the Mu Opioid Receptor.
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-03-29 DOI: 10.1021/acschemneuro.5c00140
Konstantinos Plakas, Chia-Ju Hsieh, Dinahlee Saturnino Guarino, Catherine Hou, Wai-Kit Chia, Anthony Young, Alexander Schmitz, Yi-Pei Ho, Chi-Chang Weng, Hsiaoju Lee, Shihong Li, Thomas J A Graham, Robert H Mach

The opioid crisis is a catastrophic health emergency catalyzed by the misuse of opioids that target and activate the mu opioid receptor. Many traditional radioligands used to study the mu opioid receptor are often tightly regulated owing to their abuse and respiratory depression potential. Of those that are not regulated, a lack of opioid receptor subtype selectivity can cause confounding in interpreting results. In the present study, we sought to design and characterize a library of 24 antagonist ligands for the mu opioid receptor. Ligands were evaluated for the binding affinity, intrinsic activity, and predicted blood-brain barrier permeability. Several ligands demonstrated single-digit nM binding affinity for the mu opioid receptor while also demonstrating selectivity over the delta and kappa opioid receptors. The antagonist behavior of 1A and 3A at the mu opioid receptor indicate that these ligands would likely not induce opioid-dependent respiratory depression. Therefore, these ligands can enable a safer means to interrogate the endogenous opioid system. Based on binding affinity, selectivity, and potential off-target binding, [11C]1A was prepared via metallophotoredox of the aryl-bromide functional group to [11C]methyl iodide. The nascent radioligand demonstrated brain uptake in a rhesus macaque model and accumulation in the caudate and putamen. Naloxone was able to reduce [11C]1A binding, though the interactions were not as pronounced as naloxone's ability to displace [11C]carfentanil. These results suggest that GSK1521498 and related congeners are amenable to radioligand design and can offer a safer way to query opioid neurobiology.

{"title":"Toward a Small-Molecule Antagonist Radioligand for Positron Emission Tomography Imaging of the Mu Opioid Receptor.","authors":"Konstantinos Plakas, Chia-Ju Hsieh, Dinahlee Saturnino Guarino, Catherine Hou, Wai-Kit Chia, Anthony Young, Alexander Schmitz, Yi-Pei Ho, Chi-Chang Weng, Hsiaoju Lee, Shihong Li, Thomas J A Graham, Robert H Mach","doi":"10.1021/acschemneuro.5c00140","DOIUrl":"10.1021/acschemneuro.5c00140","url":null,"abstract":"<p><p>The opioid crisis is a catastrophic health emergency catalyzed by the misuse of opioids that target and activate the mu opioid receptor. Many traditional radioligands used to study the mu opioid receptor are often tightly regulated owing to their abuse and respiratory depression potential. Of those that are not regulated, a lack of opioid receptor subtype selectivity can cause confounding in interpreting results. In the present study, we sought to design and characterize a library of 24 antagonist ligands for the mu opioid receptor. Ligands were evaluated for the binding affinity, intrinsic activity, and predicted blood-brain barrier permeability. Several ligands demonstrated single-digit nM binding affinity for the mu opioid receptor while also demonstrating selectivity over the delta and kappa opioid receptors. The antagonist behavior of <b>1A</b> and <b>3A</b> at the mu opioid receptor indicate that these ligands would likely not induce opioid-dependent respiratory depression. Therefore, these ligands can enable a safer means to interrogate the endogenous opioid system. Based on binding affinity, selectivity, and potential off-target binding, [<sup>11</sup>C]<b>1A</b> was prepared via metallophotoredox of the aryl-bromide functional group to [<sup>11</sup>C]methyl iodide. The nascent radioligand demonstrated brain uptake in a rhesus macaque model and accumulation in the caudate and putamen. Naloxone was able to reduce [<sup>11</sup>C]<b>1A</b> binding, though the interactions were not as pronounced as naloxone's ability to displace [<sup>11</sup>C]carfentanil. These results suggest that GSK1521498 and related congeners are amenable to radioligand design and can offer a safer way to query opioid neurobiology.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741719","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}
引用次数: 0
Brain Metabolite Profiles are Associated with Selective Neuronal Vulnerability and Underlying Mechanisms in Amyotrophic Lateral Sclerosis.
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-03-29 DOI: 10.1021/acschemneuro.4c00593
Enam Alhagh Gorgich, Zahra Heidari, Hamidreza Mahmoudzadeh-Sagheb, Auob Rustamzadeh, Arash Shabani, Ali Amirzadeh, Bahram Haghi Ashtiani

Amyotrophic lateral sclerosis (ALS) is a lethal neurological syndrome accompanied by selective degeneration of somatic motor neurons and neurochemistry alterations. Nevertheless, eye movement's nuclei are relatively spared from ALS damage. This survey was to probe metabolite changes in the primary motor cortex (PMC) and interstitial nucleus of Cajal (INC) of ALS patients using proton magnetic resonance spectroscopy (1H-MRS). In this case-control study, 20 patients with ALS and 20 healthy controls underwent 1.5 T MRI and multivoxel 1H-MRS. 1H-MRS spectra to determine metabolite profiles including tNAA, mIns, tCr, tCho, and also tNAA/tCr, tNAA/tCho, and mIns/tNAA metabolite ratios from the PMC and INC were quantified via a point resolved spectroscopy pulse (PRESS) sequence in two groups. Further, the associations between 1H-MRS markers with forced vital capacity (FVC), ALS functional rating scale (ALSFRS-R), and disease progression rate (ΔFS) were investigated. In the PMC, tNAA and tNAA/tCr were significantly lower in ALS patients than the healthy controls, but mIns and mIns/tNAA were significantly greater in these patients (p < 0.05). In the INC, tCho and mIns concentrations, and mIns/tNAA ratio were significantly increased (p < 0.05) in ALS patients, while tNAA and tNAA/tCr ratio did not show significant discriminations between the two groups (p > 0.05). The PMC tNAA/Cr ratio is associated with ALSFRS-R (p = 0.001, r = 0.71), FVC (p = 0.03, r = 0.58), and ΔFS (p = 0.01, r = -0.33). The mIns/tNAA ratio in PMC is also associated with ΔFS (p = 0.02, r = 0.41). In the INC, tCho concentrations (p = 0.04, r = -0.54) and mIns/tNAA ratio (p = 0.02, r = -0.38) were negatively associated with ALSFRS-R and positively correlated with ΔFS (p = 0.01, r = 0.33) and (p = 0.001, r = 0.61), respectively. The study suggests that neurochemistry changes in ALS patients' brains are linked to selective neuronal vulnerability and the underlying pathophysiology of the disease.

{"title":"Brain Metabolite Profiles are Associated with Selective Neuronal Vulnerability and Underlying Mechanisms in Amyotrophic Lateral Sclerosis.","authors":"Enam Alhagh Gorgich, Zahra Heidari, Hamidreza Mahmoudzadeh-Sagheb, Auob Rustamzadeh, Arash Shabani, Ali Amirzadeh, Bahram Haghi Ashtiani","doi":"10.1021/acschemneuro.4c00593","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00593","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a lethal neurological syndrome accompanied by selective degeneration of somatic motor neurons and neurochemistry alterations. Nevertheless, eye movement's nuclei are relatively spared from ALS damage. This survey was to probe metabolite changes in the primary motor cortex (PMC) and interstitial nucleus of Cajal (INC) of ALS patients using proton magnetic resonance spectroscopy (<sup>1</sup>H-MRS). In this case-control study, 20 patients with ALS and 20 healthy controls underwent 1.5 T MRI and multivoxel <sup>1</sup>H-MRS. <sup>1</sup>H-MRS spectra to determine metabolite profiles including tNAA, mIns, tCr, tCho, and also tNAA/tCr, tNAA/tCho, and mIns/tNAA metabolite ratios from the PMC and INC were quantified via a point resolved spectroscopy pulse (PRESS) sequence in two groups. Further, the associations between <sup>1</sup>H-MRS markers with forced vital capacity (FVC), ALS functional rating scale (ALSFRS-R), and disease progression rate (ΔFS) were investigated. In the PMC, tNAA and tNAA/tCr were significantly lower in ALS patients than the healthy controls, but mIns and mIns/tNAA were significantly greater in these patients (<i>p</i> < 0.05). In the INC, tCho and mIns concentrations, and mIns/tNAA ratio were significantly increased (<i>p</i> < 0.05) in ALS patients, while tNAA and tNAA/tCr ratio did not show significant discriminations between the two groups (<i>p</i> > 0.05). The PMC tNAA/Cr ratio is associated with ALSFRS-R (<i>p</i> = 0.001, <i>r</i> = 0.71), FVC (<i>p</i> = 0.03, <i>r</i> = 0.58), and ΔFS (<i>p</i> = 0.01, <i>r</i> = -0.33). The mIns/tNAA ratio in PMC is also associated with ΔFS (<i>p</i> = 0.02, <i>r</i> = 0.41). In the INC, tCho concentrations (<i>p</i> = 0.04, <i>r</i> = -0.54) and mIns/tNAA ratio (<i>p</i> = 0.02, <i>r</i> = -0.38) were negatively associated with ALSFRS-R and positively correlated with ΔFS (<i>p</i> = 0.01, <i>r</i> = 0.33) and (<i>p</i> = 0.001, <i>r</i> = 0.61), respectively. The study suggests that neurochemistry changes in ALS patients' brains are linked to selective neuronal vulnerability and the underlying pathophysiology of the disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741715","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}
引用次数: 0
Uncovering Amyloid-β Interactions: Gray versus White Matter.
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-03-27 DOI: 10.1021/acschemneuro.4c00439
Gabriel Cathoud, Mohtadin Hashemi, Yuri Lyubchenko, Pedro Simões

Alzheimer's disease is characterized by the accumulation of amyloid plaques in the brain. Recent studies suggest that amyloid-β (Aβ) peptides interact with cell membranes, potentially catalyzing plaque formation. However, the effect of varying cell membrane compositions on this catalytic process requires further investigation. Using molecular dynamics simulations, we demonstrate that a model gray matter membrane significantly influences the secondary structure of β-amyloid peptides. Notably, residues Asp1 and Glu22 play crucial roles in the membrane interaction. Glutamic acid at position 22, located in the middle of the peptide chain, appears to promote the formation of β-hairpin conformations, which are critical for aggregation. Additionally, our simulations reveal that the model white matter membrane allows a spontaneous insertion of segments of the peptide into the membrane, suggesting that membrane interaction not only alters the peptide structure but may also compromise membrane integrity. Our results show that the different membrane compositions in the brain may play different roles when interacting with β-amyloid peptides.

{"title":"Uncovering Amyloid-β Interactions: Gray versus White Matter.","authors":"Gabriel Cathoud, Mohtadin Hashemi, Yuri Lyubchenko, Pedro Simões","doi":"10.1021/acschemneuro.4c00439","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00439","url":null,"abstract":"<p><p>Alzheimer's disease is characterized by the accumulation of amyloid plaques in the brain. Recent studies suggest that amyloid-β (Aβ) peptides interact with cell membranes, potentially catalyzing plaque formation. However, the effect of varying cell membrane compositions on this catalytic process requires further investigation. Using molecular dynamics simulations, we demonstrate that a model gray matter membrane significantly influences the secondary structure of β-amyloid peptides. Notably, residues Asp1 and Glu22 play crucial roles in the membrane interaction. Glutamic acid at position 22, located in the middle of the peptide chain, appears to promote the formation of β-hairpin conformations, which are critical for aggregation. Additionally, our simulations reveal that the model white matter membrane allows a spontaneous insertion of segments of the peptide into the membrane, suggesting that membrane interaction not only alters the peptide structure but may also compromise membrane integrity. Our results show that the different membrane compositions in the brain may play different roles when interacting with β-amyloid peptides.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717572","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}
引用次数: 0
Induction of Ferroptotic Cell Death by Neuromelanin Pigments in Dopaminergic Cells.
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-03-27 DOI: 10.1021/acschemneuro.5c00029
Gizem Kaftan Öcal, Güliz Armagan

Neuromelanin (NM) is an iron-rich, insoluble brown or black pigment that exhibits protective properties. However, its accumulation over time may render it a source of free radicals. In Parkinson's disease, dopaminergic neurons with the highest NM levels and increased iron content are preferentially vulnerable to degeneration. Considering NM's iron binding capacity and the critical role of iron in ferroptosis, we aimed to investigate the interplay between neuromelanin and ferroptosis in dopaminergic cells. We prepared two NM pigments: iron-free NM (ifNM) and iron-containing NM (Fe3+NM) and, exposed to cells. After verifying NM accumulation, cell viability was assessed in the absence or presence of antioxidants (NAC (1 mM), Trolox (100 μM)) and specific inhibitors of cell death types. Ferroptosis-related parameters, including lipid peroxidation byproducts (4-HNE), lipid ROS, glutathione, intracellular iron, GPX4, and ACSL4, and cellular iron metabolism-related proteins (TfR1, ferroportin, ferritin, IREB2) were evaluated following ifNM and Fe3+NM treatments, with or without Ferrostatin-1, Liproxstatin-1 and deferoxamine. Both NMs induced cell death via distinct mechanisms. Ferroptotic cell death by ifNM and Fe3+NM was reversed by ferrostatin-1 and NAC (p < 0.05). Significant alterations in lipid peroxidation, GPX4 levels, and iron metabolism were observed independent of NM's iron composition (p < 0.05). Ferritin levels increased following ifNM treatment, reflecting an adaptive response to iron overload, while Fe3+NM treatment led to ferritin depletion, possibly via ferritinophagy. Our findings reveal a distinct role of iron-rich and iron-free neuromelanin in modulating ferroptotic pathways, highlighting the potential of targeting neuromelanin-iron interactions as a therapeutic strategy to mitigate neuronal ferroptosis in Parkinson's disease.

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引用次数: 0
Troglitazone as a Novel Nrf2 Activator to Attenuate Oxidative Stress and Exert Neuroprotection.
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-03-26 DOI: 10.1021/acschemneuro.5c00163
Linjie Zhang, Shuang Wang, Yanxia Zhang, Xiaopeng Zhang, Junmin Xi, Jun Wu, Jianguo Fang, Haiyu Zhao, Baoxin Zhang

Nuclear factor erythroid 2 related factor 2 (Nrf2) is closely associated with neurodegenerative diseases, and the Nrf2-mediated activation of antioxidant response elements (AREs) brings about validated strategies for treating neurodegenerative diseases. Here, we discovered that troglitazone, a clinical medication for diabetes mellitus, could serve as a Nrf2 activator to rescue neuronal damages both in vitro and in vivo. The mechanism of troglitazone action involves binding with kelch-like ECH-associated protein 1 (Keap1) and the activation of Nrf2. This process leads to the migration of Nrf2 to the cell nucleus and transactivates the AREs. Troglitazone exhibits significant alleviation of oxidative stress in PC12 cells induced by hydrogen peroxide or 6-hydroxydopamine (6-OHDA). In vivo studies indicate that troglitazone could rescue the motor activity and neurodevelopmental deficiency in zebrafish induced by 6-OHDA. Additionally, mass spectrometry imaging demonstrates that troglitazone could cross the zebrafish blood-brain barrier, supporting the application of troglitazone in treating neurodegenerative diseases. Overall, this work reveals that the novel Nrf2 activator troglitazone has potential therapeutic value for neurodegeneration and provides a foundation for its repurposing.

{"title":"Troglitazone as a Novel Nrf2 Activator to Attenuate Oxidative Stress and Exert Neuroprotection.","authors":"Linjie Zhang, Shuang Wang, Yanxia Zhang, Xiaopeng Zhang, Junmin Xi, Jun Wu, Jianguo Fang, Haiyu Zhao, Baoxin Zhang","doi":"10.1021/acschemneuro.5c00163","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00163","url":null,"abstract":"<p><p>Nuclear factor erythroid 2 related factor 2 (Nrf2) is closely associated with neurodegenerative diseases, and the Nrf2-mediated activation of antioxidant response elements (AREs) brings about validated strategies for treating neurodegenerative diseases. Here, we discovered that troglitazone, a clinical medication for diabetes mellitus, could serve as a Nrf2 activator to rescue neuronal damages both in vitro and in vivo. The mechanism of troglitazone action involves binding with kelch-like ECH-associated protein 1 (Keap1) and the activation of Nrf2. This process leads to the migration of Nrf2 to the cell nucleus and transactivates the AREs. Troglitazone exhibits significant alleviation of oxidative stress in PC12 cells induced by hydrogen peroxide or 6-hydroxydopamine (6-OHDA). In vivo studies indicate that troglitazone could rescue the motor activity and neurodevelopmental deficiency in zebrafish induced by 6-OHDA. Additionally, mass spectrometry imaging demonstrates that troglitazone could cross the zebrafish blood-brain barrier, supporting the application of troglitazone in treating neurodegenerative diseases. Overall, this work reveals that the novel Nrf2 activator troglitazone has potential therapeutic value for neurodegeneration and provides a foundation for its repurposing.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707763","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}
引用次数: 0
Morphine-Induced Antinociception Is Potentiated and Dopamine Elevations Are Inhibited by the Biased Kappa Opioid Receptor Agonist Triazole 1.1
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-03-25 DOI: 10.1021/acschemneuro.5c0007510.1021/acschemneuro.5c00075
Emanuel F. Lopes, Alyssa M. West, Jason L. Locke, Katherine Holleran, Leighelle A. Adrian, Monica H. Dawes, Alyson M. Curry, Harlie A. McKelvey, Thomas Martin and Sara R. Jones*, 

Traditional analgesic opioid compounds, which act through μ opioid receptors (MORs), engender a high risk for misuse and dependence. κ opioid receptor (KOR) activation, a potential target for pain treatment, produces antinociception without euphoric side effects but results in dysphoria and aversion. Triazole 1.1 is a KOR agonist biased toward G-protein coupled signaling, potentially promoting antinociception without dysphoria. We tested whether triazole 1.1 could provide antinociception and its effects in combination with morphine. We employed a lactic acid abdominal pain model, which induced acute pain behaviors, decreased basal dopamine levels in the nucleus accumbens (NAc), and increased KOR function. We administered several interventions including triazole 1.1 (30 mg/kg) and morphine (12 or 24 mg/kg), individually and in combination. Triazole 1.1 alone reduced the pain behavioral response and changes to KOR function but did not prevent the reduction in basal dopamine levels. Morphine not only dose-dependently prevented behavioral pain responses but also elevated NAc dopamine and did not prevent the pain-induced increase in KOR function. However, combining low-dose morphine with triazole 1.1 prevents behavioral pain responses, changes to NAc dopamine levels, and changes to KOR function. Therefore, we present triazole 1.1 as a dose-sparing pain treatment to be used in combination with a lower dose of morphine, thus reducing the potential for opioid misuse.

{"title":"Morphine-Induced Antinociception Is Potentiated and Dopamine Elevations Are Inhibited by the Biased Kappa Opioid Receptor Agonist Triazole 1.1","authors":"Emanuel F. Lopes,&nbsp;Alyssa M. West,&nbsp;Jason L. Locke,&nbsp;Katherine Holleran,&nbsp;Leighelle A. Adrian,&nbsp;Monica H. Dawes,&nbsp;Alyson M. Curry,&nbsp;Harlie A. McKelvey,&nbsp;Thomas Martin and Sara R. Jones*,&nbsp;","doi":"10.1021/acschemneuro.5c0007510.1021/acschemneuro.5c00075","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00075https://doi.org/10.1021/acschemneuro.5c00075","url":null,"abstract":"<p >Traditional analgesic opioid compounds, which act through μ opioid receptors (MORs), engender a high risk for misuse and dependence. κ opioid receptor (KOR) activation, a potential target for pain treatment, produces antinociception without euphoric side effects but results in dysphoria and aversion. Triazole 1.1 is a KOR agonist biased toward G-protein coupled signaling, potentially promoting antinociception without dysphoria. We tested whether triazole 1.1 could provide antinociception and its effects in combination with morphine. We employed a lactic acid abdominal pain model, which induced acute pain behaviors, decreased basal dopamine levels in the nucleus accumbens (NAc), and increased KOR function. We administered several interventions including triazole 1.1 (30 mg/kg) and morphine (12 or 24 mg/kg), individually and in combination. Triazole 1.1 alone reduced the pain behavioral response and changes to KOR function but did not prevent the reduction in basal dopamine levels. Morphine not only dose-dependently prevented behavioral pain responses but also elevated NAc dopamine and did not prevent the pain-induced increase in KOR function. However, combining low-dose morphine with triazole 1.1 prevents behavioral pain responses, changes to NAc dopamine levels, and changes to KOR function. Therefore, we present triazole 1.1 as a dose-sparing pain treatment to be used in combination with a lower dose of morphine, thus reducing the potential for opioid misuse.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 7","pages":"1377–1387 1377–1387"},"PeriodicalIF":4.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746006","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}
引用次数: 0
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ACS Chemical Neuroscience
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