bims-medebr 2023-05-28 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒05‒28
25 papers selected by
Regina F. Fernández
Johns Hopkins University

Astrocyte glycogen is a major source of hypothalamic lactate in rats with recurrent hypoglycemia.
Glycolytically impaired Drosophila glial cells fuel neural metabolism via β-oxidation.
GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Old Mice Improves Brain Glutathione Deficiency, Oxidative Stress, Glucose Uptake, Mitochondrial Dysfunction, Genomic Damage, Inflammation and Neurotrophic Factors to Reverse Age-Associated Cognitive Decline: Implications for Improving Brain Health in Aging.
Roles of ApoE4 on the Pathogenesis in Alzheimer's Disease and the Potential Therapeutic Approaches.
Role of Microglial Metabolic Reprogramming in Parkinson's Disease.
Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models.
The role of the PLA2G6 gene in neurodegenerative diseases.
Age-associated change in pyruvate metabolism investigated with hyperpolarized 13 C-MRI of the human brain.
Glucose metabolism impairment in Parkinson's disease.
Oxidative Stress and Neurodegeneration in Animal Models of Seizures and Epilepsy.
Polyunsaturated Fatty Acids: Conversion to Lipid Mediators, Roles in Inflammatory Diseases and Dietary Sources.
Carbon Nanodots Attenuate Lipid Peroxidation in the LDL Receptor Knockout Mouse Brain.
Infantile Neurodegeneration Results from Mutants of 17β-Hydroxysteroid Dehydrogenase Type 10 Rather Than Aβ-Binding Alcohol Dehydrogenase.
Impact of FADS gene variation and dietary fatty acid exposure on biochemical and anthropomorphic phenotypes in a Hispanic/Latino cohort.
Increasing brain N-acetylneuraminic acid alleviates hydrocephalus-induced neurological deficits.
Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System.
GM1 Oligosaccharide Efficacy in Parkinson's Disease: Protection against MPTP.
Sphingolipids in Cerebrospinal Fluid and Plasma Lipoproteins of APOE4 Homozygotes and Non-APOE4 Carriers with Mild Cognitive Impairment versus Subjective Cognitive Decline.
ASC Transporters Mediate D-Serine Transport into Astrocytes Adjacent to Synapses in the Mouse Brain.
Mapping metabolite change in the mouse brain after esketamine injection by ambient mass spectrometry imaging and metabolomics.
Metabolism of sphingadiene and characterization of the sphingadiene-producing enzyme FADS3.
Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease.
The inhibition of Aurora A kinase regulates phospholipid remodeling by upregulating LPCAT1 in glioblastoma.
Glycolipids in Parkinson's disease: beyond neuronal function.
Role of lipid nanodomains for inhibitory FcγRIIb function.

Diabetes. 2023 May 22. pii: db220902. [Epub ahead of print]

Astrocyte glycogen is a major source of hypothalamic lactate in rats with recurrent hypoglycemia.

Gong Su, Rawad Farhat, Anil K Laxman, Kimberly Chapman-Natewa, Irvane E Nelson, Owen Chan.

Lactate is an important metabolic substrate for sustaining brain energy requirements when glucose supplies are limited. Recurring exposure to hypoglycemia (RH) raises lactate levels in the ventromedial hypothalamus (VMH) which contributes to counter-regulatory failure. However, the source of this lactate remains unclear. The present study investigates whether astrocytic glycogen serves as the major source of lactate in the VMH of RH rats. By decreasing the expression of a key lactate transporter in VMH astrocytes of RH rats, we reduced extracellular lactate concentrations, suggesting excess lactate was locally produced from astrocytes. To determine whether astrocytic glycogen serves as the major source of lactate, we chronically delivered either artificial extracellular fluid or 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) to inhibit glycogen turnover in the VMH of RH animals. Inhibiting glycogen turnover in RH animals prevented the rise in VMH lactate and the development of counter-regulatory failure. Lastly, we noted that RH led to an increase in glycogen shunt activity in response to hypoglycemia and elevated glycogen phosphorylase activity in the hours following a bout of hypoglycemia. Our data suggests that dysregulation of astrocytic glycogen metabolism following recurring exposure to hypoglycemia may be responsible, at least in part, for the rise in VMH lactate levels.

DOI: https://doi.org/10.2337/db22-0902
Nat Commun. 2023 May 24. 14(1): 2996

Glycolytically impaired Drosophila glial cells fuel neural metabolism via β-oxidation.

Ellen McMullen, Helen Hertenstein, Katrin Strassburger, Leon Deharde, Marko Brankatschk, Stefanie Schirmeier.

Neuronal function is highly energy demanding and thus requires efficient and constant metabolite delivery by glia. Drosophila glia are highly glycolytic and provide lactate to fuel neuronal metabolism. Flies are able to survive for several weeks in the absence of glial glycolysis. Here, we study how Drosophila glial cells maintain sufficient nutrient supply to neurons under conditions of impaired glycolysis. We show that glycolytically impaired glia rely on mitochondrial fatty acid breakdown and ketone body production to nourish neurons, suggesting that ketone bodies serve as an alternate neuronal fuel to prevent neurodegeneration. We show that in times of long-term starvation, glial degradation of absorbed fatty acids is essential to ensure survival of the fly. Further, we show that Drosophila glial cells act as a metabolic sensor and can induce mobilization of peripheral lipid stores to preserve brain metabolic homeostasis. Our study gives evidence of the importance of glial fatty acid degradation for brain function, and survival, under adverse conditions in Drosophila.

DOI: https://doi.org/10.1038/s41467-023-38813-x
Antioxidants (Basel). 2023 May 04. pii: 1042. [Epub ahead of print]12(5):

GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Old Mice Improves Brain Glutathione Deficiency, Oxidative Stress, Glucose Uptake, Mitochondrial Dysfunction, Genomic Damage, Inflammation and Neurotrophic Factors to Reverse Age-Associated Cognitive Decline: Implications for Improving Brain Health in Aging.

Premranjan Kumar, Ob W Osahon, Rajagopal V Sekhar.

  Cognitive decline frequently occurs with increasing age, but mechanisms contributing to age-associated cognitive decline (ACD) are not well understood and solutions are lacking. Understanding and reversing mechanisms contributing to ACD are important because increased age is identified as the single most important risk factor for dementia. We reported earlier that ACD in older humans is associated with glutathione (GSH) deficiency, oxidative stress (OxS), mitochondrial dysfunction, glucose dysmetabolism and inflammation, and that supplementing GlyNAC (glycine and N-acetylcysteine) improved these defects. To test whether these defects occur in the brain in association with ACD, and could be improved/reversed with GlyNAC supplementation, we studied young (20-week) and old (90-week) C57BL/6J mice. Old mice received either regular or GlyNAC supplemented diets for 8 weeks, while young mice received the regular diet. Cognition and brain outcomes (GSH, OxS, mitochondrial energetics, autophagy/mitophagy, glucose transporters, inflammation, genomic damage and neurotrophic factors) were measured. Compared to young mice, the old-control mice had significant cognitive impairment and multiple brain defects. GlyNAC supplementation improved/corrected the brain defects and reversed ACD. This study finds that naturally-occurring ACD is associated with multiple abnormalities in the brain, and provides proof-of-concept that GlyNAC supplementation corrects these defects and improves cognitive function in aging.

Keywords:  GlyNAC supplementation; aging; brain health; cognitive improvement

DOI:  https://doi.org/10.3390/antiox12051042
Cell Mol Neurobiol. 2023 May 25.

Roles of ApoE4 on the Pathogenesis in Alzheimer's Disease and the Potential Therapeutic Approaches.

Yu-Ying Sun, Zhun Wang, Han-Chang Huang.

  The Apolipoprotein E ε4 (ApoE ε4) allele, encoding ApoE4, is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). Emerging epidemiological evidence indicated that ApoE4 contributes to AD through influencing β-amyloid (Aβ) deposition and clearance. However, the molecular mechanisms of ApoE4 involved in AD pathogenesis remains unclear. Here, we introduced the structure and functions of ApoE isoforms, and then we reviewed the potential mechanisms of ApoE4 in the AD pathogenesis, including the effect of ApoE4 on Aβ pathology, and tau phosphorylation, oxidative stress; synaptic function, cholesterol transport, and mitochondrial dysfunction; sleep disturbances and cerebrovascular integrity in the AD brains. Furthermore, we discussed the available strategies for AD treatments that target to ApoE4. In general, this review overviews the potential roles of ApoE4 in the AD development and suggests some therapeutic approaches for AD. ApoE4 is genetic risk of AD. ApoE4 is involved in the AD pathogenesis. Aβ deposition, NFT, oxidative stress, abnormal cholesterol, mitochondrial dysfunction and neuroinflammation could be observed in the brains with ApoE4. Targeting the interaction of ApoE4 with the AD pathology is available strategy for AD treatments.

Keywords:  Alzheimer’s disease (AD); Apolipoprotein E4 (ApoE4); Therapy; β-Amyloid (Aβ)

DOI:  https://doi.org/10.1007/s10571-023-01365-1
Biochem Pharmacol. 2023 May 19. pii: S0006-2952(23)00210-1. [Epub ahead of print] 115619

Role of Microglial Metabolic Reprogramming in Parkinson's Disease.

Zheng-Ping Huang, Shu-Fen Liu, Jian-Long Zhuang, Lin-Yi Li, Mi-Mi Li, Ya-Li Huang, Yan-Hong Chen, Xiang-Rong Chen, Shu Lin, Li-Chao Ye, Chun-Nuan Chen.

  Parkinson's disease (PD) is a common age-related neurodegenerative disorder characterized by damage to nigrostriatal dopaminergic neurons. Key pathogenic mechanisms underlying PD include alpha-synuclein misfolding and aggregation, impaired protein clearance, mitochondrial dysfunction, oxidative stress, and neuroinflammation. However, to date, no study has confirmed the specific pathogenesis of PD. Similarly, current PD treatment methods still have shortcomings. Although some emerging therapies have proved effective for PD, the specific mechanism still needs further clarification. Metabolic reprogramming, a term first proposed by Warburg, is applied to the metabolic energy characteristics of tumor cells. Microglia have similar metabolic characteristics. Pro-inflammatory M1 type and anti-inflammatory M2 type are the two types of activated microglia, which exhibit different metabolic patterns in glucose, lipid, amino acid, and iron metabolism. Additionally, mitochondrial dysfunction may be involved in microglial metabolic reprogramming by activating various signaling mechanisms. Functional changes in microglia resulting from metabolic reprogramming can cause changes in the brain microenvironment, thus playing an important role in neuroinflammation or tissue repair. The involvement of microglial metabolic reprogramming in PD pathogenesis has been confirmed. Neuroinflammation and dopaminergic neuronal death can effectively be reduced by inhibiting certain metabolic pathways in M1 microglia or reverting M1 cells to the M2 phenotype. This review summarizes the relationship between microglial metabolic reprogramming and PD and provides strategies for PD treatment.

Keywords:  Metabolic reprogramming; Microglia; Mitochondria; Neuroinflammation; Parkinson's disease; Signaling pathway

DOI:  https://doi.org/10.1016/j.bcp.2023.115619
Biomolecules. 2023 May 19. pii: 863. [Epub ahead of print]13(5):

Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models.

Katarina Maksimovic, Mohieldin Youssef, Justin You, Hoon-Ki Sung, Jeehye Park.

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs. While ALS-affected muscle tissue exhibits elevated energy demand and a fuel preference switch from glycolysis to fatty acid oxidation, adipose tissue in ALS undergoes increased lipolysis. Dysfunctions in the liver and pancreas contribute to impaired glucose homeostasis and insulin secretion. The central nervous system (CNS) displays abnormal glucose regulation, mitochondrial dysfunction, and increased oxidative stress. Importantly, the hypothalamus, a brain region that controls whole-body metabolism, undergoes atrophy associated with pathological aggregates of TDP-43. This review will also cover past and present treatment options that target metabolic dysfunction in ALS and provide insights into the future of metabolism research in ALS.

Keywords:  amyotrophic lateral sclerosis; hypermetabolism; metabolic dysfunction

DOI:  https://doi.org/10.3390/biom13050863
Ageing Res Rev. 2023 May 24. pii: S1568-1637(23)00116-2. [Epub ahead of print] 101957

The role of the PLA2G6 gene in neurodegenerative diseases.

Xinyue Deng, Lamei Yuan, Joseph Jankovic, Hao Deng.

  PLA2G6-associated neurodegeneration (PLAN) represents a continuum of clinically and genetically heterogeneous neurodegenerative disorders with overlapping features. Usually, it encompasses three autosomal recessive diseases, including infantile neuroaxonal dystrophy or neurodegeneration with brain iron accumulation (NBIA) 2A, atypical neuronal dystrophy with childhood-onset or NBIA2B, and adult-onset dystonia-parkinsonism form named PARK14, and possibly a certain subtype of hereditary spastic paraplegia. PLAN is caused by variants in the phospholipase A2 group VI gene (PLA2G6), which encodes an enzyme involved in membrane homeostasis, signal transduction, mitochondrial dysfunction, and α-synuclein aggregation. In this review, we discuss PLA2G6 gene structure and protein, functional findings, genetic deficiency models, various PLAN disease phenotypes, and study strategies in the future. Our primary aim is to provide an overview of genotype-phenotype correlations of PLAN subtypes and speculate on the role of PLA2G6 in potential mechanisms underlying these conditions.

Keywords:  Genetics; Neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation; Neurodegenerative disorders; PLA2G6 gene; Parkinsonism

DOI:  https://doi.org/10.1016/j.arr.2023.101957
Hum Brain Mapp. 2023 May 23.

Age-associated change in pyruvate metabolism investigated with hyperpolarized 13 C-MRI of the human brain.

Biranavan Uthayakumar, Hany Soliman, Nadia D Bragagnolo, Nicole I C Cappelletto, Casey Y Lee, Benjamin Geraghty, Albert P Chen, William J Perks, Nathan Ma, Chris Heyn, Ruby Endre, Bradley J MacIntosh, Greg J Stanisz, Sandra E Black, Charles H Cunningham.

  In this study, hyperpolarized 13 C MRI (HP-13 C MRI) was used to investigate changes in the uptake and metabolism of pyruvate with age. Hyperpolarized 13 C-pyruvate was administered to healthy aging individuals (N = 35, ages 21-77) and whole-brain spatial distributions of 13 C-lactate and 13 C-bicarbonate production were measured. Linear mixed-effects regressions were performed to compute the regional percentage change per decade, showing a significant reduction in both normalized 13 C-lactate and normalized 13 C-bicarbonate production with age: - 7 % ± 2 % $$ -7\%\pm 2\% $$ per decade for 13 C-lactate and - 9 % ± 4 % $$ -9\%\pm 4\% $$ per decade for 13 C-bicarbonate. Certain regions, such as the right medial precentral gyrus, showed greater rates of change while the left caudate nucleus had a flat 13 C-lactate versus age and a slightly increasing 13 C-bicarbonate versus age. The results show that both the production of lactate (visible as 13 C-lactate signal) as well as the consumption of monocarboxylates to make acetyl-CoA (visible as 13 C-bicarbonate signal) decrease with age and that the rate of change varies by brain region.

Keywords:  MRI; aerobic glycolysis; aging; carbon-13; lactate; metabolism; parcellation

DOI:  https://doi.org/10.1002/hbm.26329
Brain Res Bull. 2023 May 18. pii: S0361-9230(23)00104-1. [Epub ahead of print]199 110672

Glucose metabolism impairment in Parkinson's disease.

Chengcheng Dai, Changhong Tan, Lili Zhao, Yi Liang, Guohui Liu, Hang Liu, Yuke Zhong, Zhihui Liu, Lijuan Mo, Xi Liu, Lifen Chen.

  Impairments in systematic and regional glucose metabolism exist in patients with Parkinson's disease (PD) at every stage of the disease course, and such impairments are associated with the incidence, progression, and special phenotypes of PD, which affect each physiological process of glucose metabolism including glucose uptake, glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and pentose phosphate shunt pathway. These impairments may be attributed to various mechanisms, such as insulin resistance, oxidative stress, abnormal glycated modification, blood-brain-barrier dysfunction, and hyperglycemia-induced damages. These mechanisms could subsequently cause excessive methylglyoxal and reactive oxygen species production, neuroinflammation, abnormal aggregation of protein, mitochondrial dysfunction, and decreased dopamine, and finally result in energy supply insufficiency, neurotransmitter dysregulation, aggregation and phosphorylation of α-synuclein, and dopaminergic neuron loss. This review discusses the glucose metabolism impairment in PD and its pathophysiological mechanisms, and briefly summarized the currently-available therapies targeting glucose metabolism impairment in PD, including glucagon-likepeptide-1 (GLP-1) receptor agonists and dual GLP-1/gastric inhibitory peptide receptor agonists, metformin, and thiazoledinediones.

Keywords:  Energy supply insufficiency; Glucose metabolism impairment; Parkinson’s disease; Pathophysiological mechanism; Therapy

DOI:  https://doi.org/10.1016/j.brainresbull.2023.110672
Antioxidants (Basel). 2023 May 05. pii: 1049. [Epub ahead of print]12(5):

Oxidative Stress and Neurodegeneration in Animal Models of Seizures and Epilepsy.

Krzysztof Łukawski, Stanisław J Czuczwar.

  Free radicals are generated in the brain, as well as in other organs, and their production is proportional to the brain activity. Due to its low antioxidant capacity, the brain is particularly sensitive to free radical damage, which may affect lipids, nucleic acids, and proteins. The available evidence clearly points to a role for oxidative stress in neuronal death and pathophysiology of epileptogenesis and epilepsy. The present review is devoted to the generation of free radicals in some animal models of seizures and epilepsy and the consequences of oxidative stress, such as DNA or mitochondrial damage leading to neurodegeneration. Additionally, antioxidant properties of antiepileptic (antiseizure) drugs and a possible use of antioxidant drugs or compounds in patients with epilepsy are reviewed. In numerous seizure models, the brain concentration of free radicals was significantly elevated. Some antiepileptic drugs may inhibit these effects; for example, valproate reduced the increase in brain malondialdehyde (a marker of lipid peroxidation) concentration induced by electroconvulsions. In the pentylenetetrazol model, valproate prevented the reduced glutathione concentration and an increase in brain lipid peroxidation products. The scarce clinical data indicate that some antioxidants (melatonin, selenium, vitamin E) may be recommended as adjuvants for patients with drug-resistant epilepsy.

Keywords:  antioxidants; epilepsy; epileptogenesis; free radicals; oxidative stress; seizures

DOI:  https://doi.org/10.3390/antiox12051049
Int J Mol Sci. 2023 May 16. pii: 8838. [Epub ahead of print]24(10):

Polyunsaturated Fatty Acids: Conversion to Lipid Mediators, Roles in Inflammatory Diseases and Dietary Sources.

John L Harwood.

  Polyunsaturated fatty acids (PUFAs) are important components of the diet of mammals. Their role was first established when the essential fatty acids (EFAs) linoleic acid and α-linolenic acid were discovered nearly a century ago. However, most of the biochemical and physiological actions of PUFAs rely on their conversion to 20C or 22C acids and subsequent metabolism to lipid mediators. As a generalisation, lipid mediators formed from n-6 PUFAs are pro-inflammatory while those from n-3 PUFAs are anti-inflammatory or neutral. Apart from the actions of the classic eicosanoids or docosanoids, many newly discovered compounds are described as Specialised Pro-resolving Mediators (SPMs) which have been proposed to have a role in resolving inflammatory conditions such as infections and preventing them from becoming chronic. In addition, a large group of molecules, termed isoprostanes, can be generated by free radical reactions and these too have powerful properties towards inflammation. The ultimate source of n-3 and n-6 PUFAs are photosynthetic organisms which contain Δ-12 and Δ-15 desaturases, which are almost exclusively absent from animals. Moreover, the EFAs consumed from plant food are in competition with each other for conversion to lipid mediators. Thus, the relative amounts of n-3 and n-6 PUFAs in the diet are important. Furthermore, the conversion of the EFAs to 20C and 22C PUFAs in mammals is rather poor. Thus, there has been much interest recently in the use of algae, many of which make substantial quantities of long-chain PUFAs or in manipulating oil crops to make such acids. This is especially important because fish oils, which are their main source in human diets, are becoming limited. In this review, the metabolic conversion of PUFAs into different lipid mediators is described. Then, the biological roles and molecular mechanisms of such mediators in inflammatory diseases are outlined. Finally, natural sources of PUFAs (including 20 or 22 carbon compounds) are detailed, as well as recent efforts to increase their production.

Keywords:  docosanoids; eicosanoids; inflammation; lipid mediators; polyunsaturated fatty acids; specialised pro-resolving mediators; synthesis

DOI:  https://doi.org/10.3390/ijms24108838
Antioxidants (Basel). 2023 May 11. pii: 1081. [Epub ahead of print]12(5):

Carbon Nanodots Attenuate Lipid Peroxidation in the LDL Receptor Knockout Mouse Brain.

Keith M Erikson, Kristina El-Khouri, Radmila Petric, Chenhao Tang, Jinlan Chen, Delicia Esther Cardenas Vasquez, Steve C Fordahl, Zhenquan Jia.

  Abnormal cholesterol metabolism can lead to oxidative stress in the brain. Low-density lipoprotein receptor (LDLr) knockout mice are models for studying altered cholesterol metabolism and oxidative stress onset in the brain. Carbon nanodots are a new class of carbon nanomaterials that possess antioxidant properties. The goal of our study was to evaluate the effectiveness of carbon nanodots in preventing brain lipid peroxidation. LDLr knockout mice and wild-type C57BL/6J mice were treated with saline or 2.5 mg/kg bw of carbon nanodots for a 16-week period. Brains were removed and dissected into the cortex, midbrain, and striatum. We measured lipid peroxidation in the mouse brain tissues using the Thiobarbituric Acid Reactive Substances Assay and iron and copper concentrations using Graphite Furnace Atomic Absorption Spectroscopy. We focused on iron and copper due to their association with oxidative stress. Iron concentrations were significantly elevated in the midbrain and striatum of the LDLr knockout mice compared to the C57BL/6J mice, whereas lipid peroxidation was greatest in the midbrain and cortex of the LDLr knockout mice. Treatment with carbon nanodots in the LDLr knockout mice attenuated both the rise in iron and lipid peroxidation, but they had no negative effect in the C57BL/6J mice, indicating the anti-oxidative stress properties of carbon nanodots. We also assessed locomotor and anxiety-like behaviors as functional indicators of lipid peroxidation and found that treatment with carbon nanodots prevented the anxiety-like behaviors displayed by the LDLr knockout mice. Overall, our results show that carbon nanodots are safe and may be an effective nanomaterial for combating the harmful effects caused by lipid peroxidation.

Keywords:  brain; carbon nanodots; copper; iron; lipid peroxidation; midbrain

DOI:  https://doi.org/10.3390/antiox12051081
Int J Mol Sci. 2023 May 09. pii: 8487. [Epub ahead of print]24(10):

Infantile Neurodegeneration Results from Mutants of 17β-Hydroxysteroid Dehydrogenase Type 10 Rather Than Aβ-Binding Alcohol Dehydrogenase.

Xue-Ying He, Carl Dobkin, William Ted Brown, Song-Yu Yang.

  Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10), a homo-tetrameric multifunctional protein with 1044 residues encoded by the HSD17B10 gene, is necessary for brain cognitive function. Missense mutations result in infantile neurodegeneration, an inborn error in isoleucine metabolism. A 5-methylcytosine hotspot underlying a 388-T transition leads to the HSD10 (p.R130C) mutant to be responsible for approximately half of all cases suffering with this mitochondrial disease. Fewer females suffer with this disease due to X-inactivation. The binding capability of this dehydrogenase to Aβ-peptide may play a role in Alzheimer's disease, but it appears unrelated to infantile neurodegeneration. Research on this enzyme was complicated by reports of a purported Aβ-peptide-binding alcohol dehydrogenase (ABAD), formerly referred to as endoplasmic-reticulum-associated Aβ-binding protein (ERAB). Reports concerning both ABAD and ERAB in the literature reflect features inconsistent with the known functions of 17β-HSD10. It is clarified here that ERAB is reportedly a longer subunit of 17β-HSD10 (262 residues). 17β-HSD10 exhibits L-3-hydroxyacyl-CoA dehydrogenase activity and is thus also referred to in the literature as short-chain 3-hydorxyacyl-CoA dehydrogenase or type II 3-hydorxyacyl-CoA dehydrogenase. However, 17β-HSD10 is not involved in ketone body metabolism, as reported in the literature for ABAD. Reports in the literature referring to ABAD (i.e., 17β-HSD10) as a generalized alcohol dehydrogenase, relying on data underlying ABAD's activities, were found to be unreproducible. Furthermore, the rediscovery of ABAD/ERAB's mitochondrial localization did not cite any published research on 17β-HSD10. Clarification of the purported ABAD/ERAB function derived from these reports on ABAD/ERAB may invigorate this research field and encourage new approaches to the understanding and treatment of HSD17B10-gene-related disorders. We establish here that infantile neurodegeneration is caused by mutants of 17β-HSD10 but not ABAD, and so we conclude that ABAD represents a misnomer employed in high-impact journals.

Keywords:  X-linked; intellectual disability; mental disability; metabolic disorders; mitochondria; neurodegeneration

DOI:  https://doi.org/10.3390/ijms24108487
Front Nutr. 2023 ;10 1111624

Impact of FADS gene variation and dietary fatty acid exposure on biochemical and anthropomorphic phenotypes in a Hispanic/Latino cohort.

Susan Sergeant, Brian A Keith, Michael C Seeds, Jimaree A Legins, Caroline B Young, Mara Z Vitolins, Floyd H Chilton.

  Introduction: Polyunsaturated fatty acids (PUFA) and highly unsaturated fatty acid (HUFA) synthetic products and their signaling metabolites play vital roles in immunity, inflammation, and brain development/function. Frequency differences of variants within the fatty acid desaturase (FADS) gene cluster affect levels of HUFAs, their biologically active products, and numerous physiological phenotypes. Fundamental questions remain regarding the impact of this genetic variation on the health of Hispanic/Latino populations.Methods: Data and biospecimens (plasma, red blood cells, buffy coat-derived DNA) from 135 participants (83.7% female) were used to assess the relationship(s) between dietary PUFA levels, a FADS haplotype tagging SNP, rs174537, and the capacity of Hispanic/Latino populations to generate HUFAs in plasma and RBC as well as its potential impact on anthropomorphic phenotypes.
Results: The dietary habits of the cohort showed that participant diets contained a high ratio (9.3 ± 0.2, mean ± SEM) of linoleic acid (n-6) to alpha-linolenic acid (n-3) and also contained extremely low levels of n-3 HUFAs (eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA), both features of the Modern Western Diet. Compared to African and European American cohorts, the frequency of the TT rs174537 genotype was highly enriched (53% of subjects) in this Hispanic/Latino cohort and was strongly associated with lower circulating HUFA levels. For example, plasma levels of arachidonic acid (ARA: 20:4, n-6) and EPA (20:5, n-3) were 37% and 23%, respectively, lower in the TT versus the GG genotype. HUFA biosynthetic efficiency, as determined by metabolic product to precursor ratios, was highly dependent (p < 0.0001) on the rs174537 genotype (GG > GT > TT) for both circulating n-6 and n-3 HUFAs. In contrast, the RBC Omega-3 Index (EPA + DHA) was extremely low (2.89 ± 1.65, mean ± sd) in this population and independent of rs174537 genotype. Importantly, the rs174537 genotype was also related to female height with TT genotype participants being 4.5 cm shorter (p = 0.0001) than the GG + GT participants.
Discussion: Taken together, this study illustrates that dietary PUFA + HUFA × FADS gene- interactions place a large proportion (>50%) of Hispanic/Latino populations at high risk of a deficiency in both circulating and cellular levels of n-3 HUFAs.

Keywords:  FADS cluster; HUFA; Hispanic (demographic); Latino (Hispanic); PUFA; diet; highly unsaturated fatty acid; omega-3 HUFA deficiency

DOI:  https://doi.org/10.3389/fnut.2023.1111624
CNS Neurosci Ther. 2023 May 24.

Increasing brain N-acetylneuraminic acid alleviates hydrocephalus-induced neurological deficits.

Zhangyang Wang, Xiaoqun Nie, Fang Gao, Yanmin Tang, Yuanyuan Ma, Yiying Zhang, Yanqin Gao, Chen Yang, Jing Ding, Xin Wang.

  AIMS: This metabolomic study aimed to evaluate the role of N-acetylneuraminic acid (Neu5Ac) in the neurological deficits of normal pressure hydrocephalus (NPH) and its potential therapeutic effect.METHODS: We analyzed the metabolic profiles of NPH using cerebrospinal fluid with multivariate and univariate statistical analyses in a set of 42 NPH patients and 38 controls. We further correlated the levels of differential metabolites with severity-related clinical parameters, including the normal pressure hydrocephalus grading scale (NPHGS). We then established kaolin-induced hydrocephalus in mice and treated them using N-acetylmannosamine (ManNAc), a precursor of Neu5Ac. We examined brain Neu5Ac, astrocyte polarization, demyelination, and neurobehavioral outcomes to explore its therapeutic effect.
RESULTS: Three metabolites were significantly altered in NPH patients. Only decreased Neu5Ac levels were correlated with NPHGS scores. Decreased brain Neu5Ac levels have been observed in hydrocephalic mice. Increasing brain Neu5Ac by ManNAc suppressed the activation of astrocytes and promoted their transition from A1 to A2 polarization. ManNAc also attenuated the periventricular white matter demyelination and improved neurobehavioral outcomes in hydrocephalic mice.
CONCLUSION: Increasing brain Neu5Ac improved the neurological outcomes associated with the regulation of astrocyte polarization and the suppression of demyelination in hydrocephalic mice, which may be a potential therapeutic strategy for NPH.

Keywords:  N-acetylmannosamine; N-acetylneuraminic acid; hydrocephalus; metabolomics

DOI:  https://doi.org/10.1111/cns.14253
Biomolecules. 2023 May 11. pii: 816. [Epub ahead of print]13(5):

Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System.

Kenneth Maiese.

  It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer's disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.

Keywords:  AMP activated protein kinase (AMPK); Alzheimer’s disease; COVID-19; apolipoprotein E (APOE-ε4); autophagy; dementia; diabetes mellitus; erythropoietin; mechanistic target of rapamycin (mTOR); pyroptosis

DOI:  https://doi.org/10.3390/biom13050816
Biomedicines. 2023 Apr 28. pii: 1305. [Epub ahead of print]11(5):

GM1 Oligosaccharide Efficacy in Parkinson's Disease: Protection against MPTP.

Maria Fazzari, Giulia Lunghi, Alexandre Henriques, Noëlle Callizot, Maria Grazia Ciampa, Laura Mauri, Simona Prioni, Emma Veronica Carsana, Nicoletta Loberto, Massimo Aureli, Luigi Mari, Sandro Sonnino, Elena Chiricozzi, Erika Di Biase.

  Past evidence has shown that the exogenous administration of GM1 ganglioside slowed neuronal death in preclinical models of Parkinson's disease, a neurodegenerative disorder characterized by the progressive loss of dopamine-producing neurons: however, the physical and chemical properties of GM1 (i.e., amphiphilicity) limited its clinical application, as the crossing of the blood-brain barrier is denied. Recently, we demonstrated that the GM1 oligosaccharide head group (GM1-OS) is the GM1 bioactive portion that, interacting with the TrkA-NGF complex at the membrane surface, promotes the activation of a multivariate network of intracellular events regulating neuronal differentiation, protection, and reparation. Here, we evaluated the GM1-OS neuroprotective potential against the Parkinson's disease-linked neurotoxin MPTP, which destroys dopaminergic neurons by affecting mitochondrial bioenergetics and causing ROS overproduction. In dopaminergic and glutamatergic primary cultures, GM1-OS administration significantly increased neuronal survival, preserved neurite network, and reduced mitochondrial ROS production enhancing the mTOR/Akt/GSK3β pathway. These data highlight the neuroprotective efficacy of GM1-OS in parkinsonian models through the implementation of mitochondrial function and reduction in oxidative stress.

Keywords:  GM1 ganglioside; GM1 oligosaccharide; MPTP; Parkinson’s disease; neuroprotection; plasma membrane signaling

DOI:  https://doi.org/10.3390/biomedicines11051305
J Alzheimers Dis Rep. 2023 ;7(1): 339-354

Sphingolipids in Cerebrospinal Fluid and Plasma Lipoproteins of APOE4 Homozygotes and Non-APOE4 Carriers with Mild Cognitive Impairment versus Subjective Cognitive Decline.

Sandra den Hoedt, Kristien Y Dorst-Lagerwerf, Helga E de Vries, Annemieke J M Rozemuller, Philip Scheltens, Jochen Walter, Eric J G Sijbrands, Pilar Martinez-Martinez, Adrie J M Verhoeven, Charlotte E Teunissen, Monique T Mulder.

  Background: Alzheimer's disease (AD) patients display alterations in cerebrospinal fluid (CSF) and plasma sphingolipids. The APOE4 genotype increases the risk of developing AD.Objective: To test the hypothesis that the APOE4 genotype affects common sphingolipids in CSF and in plasma of patients with early stages of AD.
Methods: Patients homozygous for APOE4 and non-APOE4 carriers with mild cognitive impairment (MCI; n = 20 versus 20) were compared to patients with subjective cognitive decline (SCD; n = 18 versus 20). Sphingolipids in CSF and plasma lipoproteins were determined by liquid-chromatography-tandem mass spectrometry. Aβ42 levels in CSF were determined by immunoassay.
Results: APOE4 homozygotes displayed lower levels of sphingomyelin (SM; p = 0.042), SM(d18:1/18:0) (p = 0.026), and Aβ42 (p < 0.001) in CSF than non-APOE4 carriers. CSF-Aβ42 correlated with Cer(d18:1/18:0), SM(d18:1/18:0), and SM(d18:1/18:1) levels in APOE4 homozygotes (r > 0.49; p < 0.032) and with Cer(d18:1/24:1) in non-APOE4 carriers (r = 0.50; p = 0.025). CSF-Aβ42 correlated positively with Cer(d18:1/24:0) in MCI (p = 0.028), but negatively in SCD patients (p = 0.019). Levels of Cer(d18:1/22:0) and long-chain SMs were inversely correlated with Mini-Mental State Examination score among MCI patients, independent of APOE4 genotype (r< -0.47; p < 0.039). Nevertheless, age and sex are stronger determinants of individual sphingolipid levels in CSF than either the APOE genotype or the cognitive state. In HDL, ratios of Cer(d18:1/18:0) and Cer(d18:1/22:0) to cholesterol were higher in APOE4 homozygotes than in non-APOE4 carriers (p = 0.048 and 0.047, respectively).
Conclusion: The APOE4 genotype affects sphingolipid profiles of CSF and plasma lipoproteins already at early stages of AD. ApoE4 may contribute to the early development of AD through modulation of sphingolipid metabolism.

Keywords:  Alzheimer’s disease; Apolipoprotein E4; amyloid-β peptides; ceramides; cerebrospinal fluid; cognitive dysfunction; lipoproteins; sphingolipids

DOI:  https://doi.org/10.3233/ADR220072
Biomolecules. 2023 May 11. pii: 819. [Epub ahead of print]13(5):

ASC Transporters Mediate D-Serine Transport into Astrocytes Adjacent to Synapses in the Mouse Brain.

Karthik Subramanian Krishnan, Brian Billups.

  D-serine is an important signalling molecule, which activates N-methyl D-aspartate receptors (NMDARs) in conjunction with its fellow co-agonist, the neurotransmitter glutamate. Despite its involvement in plasticity and memory related to excitatory synapses, its cellular source and sink remain a question. We hypothesise that astrocytes, a type of glial cell that surrounds synapses, are likely candidates to control the extracellular concentration of D-Serine by removing it from the synaptic space. Using in situ patch clamp recordings and pharmacological manipulation of astrocytes in the CA1 region of the mouse hippocampal brain slices, we investigated the transport of D-serine across the plasma membrane. We observed the D-serine-induced transport-associated currents upon puff-application of 10 mM D-serine on astrocytes. Further, O-benzyl-L-serine and trans-4-hydroxy-proline, known substrate inhibitors of the alanine serine cysteine transporters (ASCT), reduced D-serine uptake. These results indicate that ASCT is a central mediator of astrocytic D-serine transport and plays a role in regulating its synaptic concentration by sequestration into astrocytes. Similar results were observed in astrocytes of the somatosensory cortex and Bergmann glia in the cerebellum, indicative of a general mechanism expressed across a range of brain areas. This removal of synaptic D-serine and its subsequent metabolic degradation are expected to reduce its extracellular availability, influencing NMDAR activation and NMDAR-dependent synaptic plasticity.

Keywords:  ASCT1; Bergmann glia; CA1-Schaffer collateral; NMDA; Slc1a4; Slc1a5; astrocyte; cerebellum; electrophysiology; hippocampus

DOI:  https://doi.org/10.3390/biom13050819
Front Psychiatry. 2023 ;14 1109344

Mapping metabolite change in the mouse brain after esketamine injection by ambient mass spectrometry imaging and metabolomics.

Guan-Xi Liu, Ze-Lin Li, Su-Yan Lin, Qian Wang, Zheng-Yi Luo, Kai Wu, Yan-Lin Zhou, Yu-Ping Ning.

  Ketamine is a new, fast, and effective antidepression treatment method; however, the possible dissociation effects, sensory changes, abuse risk, and the inability to accurately identify whether patients have a significant response to ketamine limit its clinical use. Further exploration of the antidepressant mechanisms of ketamine will contribute to its safe and practical application. Metabolites, the products of upstream gene expression and protein regulatory networks, play an essential role in various physiological and pathophysiological processes. In traditional metabonomics it is difficult to achieve the spatial localization of metabolites, which limits the further analysis of brain metabonomics by researchers. Here, we used a metabolic network mapping method called ambient air flow-assisted desorption electrospray ionization (AFADESI)-mass spectrometry imaging (MSI). We found the main changes in glycerophospholipid metabolism around the brain and sphingolipid metabolism changed mainly in the globus pallidus, which showed the most significant metabolite change after esketamine injection. The spatial distribution of metabolic changes was evaluated in the whole brain, and the potential mechanism of esketamine's antidepressant effect was explored in this research.

Keywords:  antidepressant; depression; ketamine; mass spectrometry imaging; spatial metabolomics

DOI:  https://doi.org/10.3389/fpsyt.2023.1109344
Biochim Biophys Acta Mol Cell Biol Lipids. 2023 May 18. pii: S1388-1981(23)00059-8. [Epub ahead of print]1868(8): 159335

Metabolism of sphingadiene and characterization of the sphingadiene-producing enzyme FADS3.

Keisuke Jojima, Akio Kihara.

  Of the long-chain bases (LCBs) that comprise the ceramides (CERs) present in mammals, only 4,14-sphingadiene (sphingadiene; SPD) has a cis double bond (at C14). Because of this unique structure, the metabolism of SPD may differ from that of other LCBs, but whether this is the case remains unclear. FADS3 is responsible for introducing the cis double bond in SPD. However, the substrate specificity of FADS3 and cofactors involved in the FADS3-catalyzed reaction are also unknown. In the present study, a cell-based assay using a ceramide synthase inhibitor and an in vitro experiment showed that FADS3 is active toward sphingosine (SPH)-containing CERs (SPH-CERs) but not toward free SPH. FADS3 exhibits specificity with respect to the chain length of the SPH moiety of SPH-CERs (active toward C16-20), but not that of the fatty acid moiety. Furthermore, FADS3 is active toward straight-chain and iso-branched-chain SPH-containing CERs but not toward anteiso-branched forms. In addition to SPH-CERs, FADS3 also shows activity toward dihydrosphingosine-containing CERs, but this activity is approximately half of that toward SPH-CERs. It uses either NADH or NADPH as an electron donor, and the electron transfer is facilitated by cytochrome b5. The metabolic flow of SPD to sphingomyelin is predominant over that to glycosphingolipids. In the metabolic pathway from SPD to fatty acids, the chain length of the SPD is reduced by two carbons and the trans double bond at C4 is saturated. This study thus elucidates the enzymatic properties of FADS3 and the metabolism of SPD.

Keywords:  4,14-Sphingadiene; Ceramide; Desaturase; Lipid metabolism; Sphingolipid

DOI:  https://doi.org/10.1016/j.bbalip.2023.159335
Alzheimers Dement. 2023 May 22.

Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease.

Daniel J Panyard, Justin McKetney, Yuetiva K Deming, Autumn R Morrow, Gilda E Ennis, Erin M Jonaitis, Carol A Van Hulle, Chengran Yang, Yun Ju Sung, Muhammad Ali, Gwendlyn Kollmorgen, Ivonne Suridjan, Anna Bayfield, Barbara B Bendlin, Henrik Zetterberg, Kaj Blennow, Carlos Cruchaga, Cynthia M Carlsson, Sterling C Johnson, Sanjay Asthana, Joshua J Coon, Corinne D Engelman.

  INTRODUCTION: A hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest.METHODS: We conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation.
RESULTS: We identified 61 proteins significantly associated with the AT category (P < 5.46 × 10-5 ) and 636 significant protein-biomarker associations (P < 6.07 × 10-6 ). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers.
DISCUSSION: These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD.
HIGHLIGHTS: Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing. Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins. Key glucose/carbon metabolism protein associations independently replicated. CSF proteome outperformed other omics data in predicting amyloid/tau positivity. CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.

Keywords:  Alzheimer's disease; acylcarnitines; amyloid; biomarkers; carbon metabolism; glucose metabolism; metabolism; metabolomics; multiomics; neurodegeneration; neuroinflammation; proteomics; tau

DOI:  https://doi.org/10.1002/alz.13130
Neoplasma. 2023 Apr;pii: 221126N1140. [Epub ahead of print]70(2): 260-271

The inhibition of Aurora A kinase regulates phospholipid remodeling by upregulating LPCAT1 in glioblastoma.

Ya-Zhou Miao, Jing Wang, Shu-Yu Hao, Yu-Xuan Deng, Zhe Zhang, Ze-Ping Jin, Da-Yuan Liu, Shao-Dong Zhang, Hong Wan, Nan Ji, Jie Feng.

Metabolic reprogramming is a common feature of glioblastoma (GBM) progression and metastasis. Altered lipid metabolism is one of the most prominent metabolic alterations in cancer. Understanding the links between phospholipid remodeling and GBM tumorigenesis may help develop new anticancer strategies and improve treatments to overcome drug resistance. We used metabolomic and transcriptomic analyses to systematically investigate metabolic and molecular changes in low-grade glioma (LGG) and GBM. We then re-established the reprogrammed metabolic flux and membrane lipid composition in GBM based on metabolomic and transcriptomic analyses. By inhibiting Aurora A kinase via RNA interference (RNAi) and inhibitor treatment, we investigated the effect of Aurora A kinase on phospholipid reprogramming LPCAT1 enzyme expression and GBM cell proliferation in vitro and in vivo. We found that GBM displayed aberrant glycerophospholipid and glycerolipid metabolism compared with LGG. Metabolic profiling indicated that fatty acid synthesis and uptake for phospholipid synthesis were significantly increased in GBM compared to LGG. The unsaturated phosphatidylcholine (PC) and phosphatidylethanolamine (PE) levels were significantly decreased in GBM compared to LGG. The expression level of LPCAT1, which is required for the synthesis of saturated PC and PE, was upregulated in GBM, and the expression of LPCAT4, which is required for the synthesis of unsaturated PC and PE, was downregulated in GBM. Notably, the inhibition of Aurora A kinase by shRNA knockdown and treatment with Aurora A kinase inhibitors such as Alisertib, AMG900, or AT9283 upregulated LPCAT1 mRNA and protein expression in vitro. In vivo, the inhibition of Aurora A kinase with Alisertib increased LPCAT1 protein expression. Phospholipid remodeling and a reduction in unsaturated membrane lipid components were found in GBM. Aurora A kinase inhibition increased LPCAT1 expression and suppressed GBM cell proliferation. The combination of Aurora kinase inhibition with LPCAT1 inhibition may exert promising synergistic effects on GBM.

DOI: https://doi.org/10.4149/neo_2023_221126N1140
FEBS Open Bio. 2023 May 23.

Glycolipids in Parkinson's disease: beyond neuronal function.

Fokion Spanos, Michela Deleidi.

  Glycolipid balance is key to normal body function, and its alteration can lead to a variety of diseases involving multiple organs and tissues. Glycolipid disturbances are also involved in Parkinson's disease (PD) pathogenesis and aging. Increasing evidence suggests that glycolipids affect cellular functions beyond the brain, including the peripheral immune system, intestinal barrier, and immunity. Hence, the interplay between aging, genetic predisposition, and environmental exposures could initiate systemic and local glycolipid changes that lead to inflammatory reactions and neuronal dysfunction. In this review, we discuss recent advances in the link between glycolipid metabolism and immune function and how these metabolic changes can exacerbate immunological contributions to neurodegenerative diseases, with a focus on PD. Further understanding of the cellular and molecular mechanisms that control glycolipid pathways and their impact on both peripheral tissues and the brain will help unravel how glycolipids shape immune and nervous system communication and the development of novel drugs to prevent PD and promote healthy aging.

Keywords:  Central Nervous System; Glycolipids; Immune system; Inflammation; Intestine; Parkinson's

DOI:  https://doi.org/10.1002/2211-5463.13651
bioRxiv. 2023 May 12. pii: 2023.05.09.540011. [Epub ahead of print]

Role of lipid nanodomains for inhibitory FcγRIIb function.

Franziska Spiegel, Marius F W Trollmann, Sibel Kara, Matthias Pöhnl, Astrid F Brandner, Falk Nimmerjahn, Anja Lux, Rainer A Böckmann.

The inhibitory Fcγ receptor FcγRIIb is involved in immune regulation and is known to localize to specific regions of the plasma membrane called lipid rafts. Previous studies suggested a link between the altered lateral receptor localization within the plasma membrane and the functional impairment of the FcγRIIb-I232T variant that is associated with systemic lupus erythematosus. Here, we conducted microsecond all-atom molecular dynamics simulations and IgG binding assays to investigate the lipid nano-environment of FcγRIIb monomers and of the FcγRIIb-I232T mutant within a plasma membrane model, the orientation of the FcγRIIb ectodomain, and its accessibility to IgG ligands. In contrast to previously proposed models, our simulations indicated that FcγRIIb does not favor a cholesterol-or a sphingolipid-enriched lipid environment. Interestingly, cholesterol was depleted for all studied FcγRIIb variants within a 2-3 nm environment of the receptor, counteracting the usage of raft terminology for models on receptor functionality. Instead, the receptor interacts with lipids that have poly-unsaturated fatty acyl chains and with (poly-) anionic lipids within the cytosolic membrane leaflet. We also found that FcγRIIb monomers adopt a conformation that is not suitable for binding to its IgG ligand, consistent with a lack of detectable binding of monomeric IgG in experiments on primary immune cells. However, our results propose that multivalent IgG complexes might stabilize FcγRIIb in a binding-competent conformation. We suggest differences in receptor complex formation within the membrane as a plausible cause of the altered membrane localization or clustering and the altered suppressive function of the FcγRIIb-I232T variant.Significance Statement: Our study sheds new light on the molecular mechanisms underlying the regulation of immune signaling mediated by the inhibitory Fcγ receptor (FcγRIIb). By utilizing atomistic simulations and experimental assays, we demonstrate that FcγRIIb interacts with specific lipids in the plasma membrane. Notably, our findings challenge the current view of membrane heterogeneity in immune cells, as FcγRIIb is not localized in specialized membrane domains known as rafts. Rather, we propose that receptor complex formation modulates receptor localization and conformation, thereby enabling ligand binding.Our findings have important implications for understanding how immune receptors function and communicate with each other, and may provide new opportunities for developing therapeutic strategies targeting FcγRIIb in diseases such as autoimmunity and cancer.

DOI: https://doi.org/10.1101/2023.05.09.540011