bims-medebr 2023-10-15 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–10–15
twenty-two papers selected by
Regina F. Fernández, Johns Hopkins University

Intermittent fasting and Alzheimer's disease-Targeting ketone bodies as a potential strategy for brain energy rescue.
Pharmacokinetic effects of a single-dose nutritional ketone ester supplement on brain ketone and glucose metabolism in alcohol use disorder - a pilot study.
Supplementation of Medium-Chain Triglycerides Combined with Docosahexaenoic Acid Inhibits Amyloid Beta Protein Deposition by Improving Brain Glucose Metabolism in APP/PS1 Mice.
The cell biology of APOE in the brain.
Role of Mitochondrial Dysfunction in Cellular Lipid Homeostasis and Disease.
Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.
Impairment of serine transport across the blood-brain barrier by deletion of Slc38a5 causes developmental delay and motor dysfunction.
Pro-resolution lipid mediator maresin-1 ameliorates inflammation, promotes neuroprotection, and prevents disease progression in experimental models of multiple sclerosis.
Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging.
Calcium signals tune AMPK activity and mitochondrial homeostasis in dendrites of developing neurons.
Glycosphingolipids are linked to elevated neurotransmission and neurodegeneration in a Drosophila model of Niemann Pick type C.
Very-long-chain fatty acids are crucial to neuronal polarity by providing sphingolipids to lipid rafts.
Schizophrenia-Like Behaviors Arising from Dysregulated Proline Metabolism Are Associated with Altered Neuronal Morphology and Function in Mice with Hippocampal PRODH Deficiency.
Guanidinoacetate N-methyltransferase deficiency: Case report and brief review of the literature.
The First Reported Case of a Child with Two Different Rare Metabolic Disorders: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency and Encephalomyopathic Mitochondrial DNA Depletion Syndrome 13.
Metabolic switch from glycogen to lipid in the liver maintains glucose homeostasis in neonatal mice.
Inhibition of the proteoglycan receptor PTPσ promotes functional recovery on a rodent model of preterm hypoxic-ischemic brain injury.
The Physiological and Pathological Role of Acyl-CoA Oxidation.
mNSCs overexpressing Rimkla transplantation facilitates cognitive recovery in a mouse model of traumatic brain injury.
Cooperative lipolytic control of neuronal triacylglycerol by spastic paraplegia-associated enzyme DDHD2 and ATGL.
Possible role of tryptophan metabolism along the microbiota-gut-brain axis on cognitive & behavioral aspects in Phenylketonuria.
Isolation of the murine Glut1 deficient thalamocortical circuit: wavelet characterization and reverse glucose dependence of low and gamma frequency oscillations.

Metab Brain Dis. 2023 Oct 12.

Intermittent fasting and Alzheimer's disease-Targeting ketone bodies as a potential strategy for brain energy rescue.

Yu- Cai Ye, Shi-Fan Chai, Xin-Ru Li, Mei-Na Wu, Hong-Yan Cai, Zhao-Jun Wang.

  Alzheimer's disease (AD) lacks effective clinical treatments. As the disease progresses, the cerebral glucose hypometabolism that appears in the preclinical phase of AD gradually worsens, leading to increasingly severe brain energy disorders. This review analyzes the brain energy deficit in AD and its etiology, brain energy rescue strategies based on ketone intervention, the effects and mechanisms of IF, the differences in efficacy between IF and ketogenic diet and the duality of IF. The evidence suggests that brain energy deficits lead to the development and progression of AD pathology. IF, which improves brain energy impairments by promoting ketone metabolism, thus has good therapeutic potential for AD.

Keywords:  Alzheimer’s disease; Brain energy rescue; Brain glucose metabolism; Intermittent fasting; Ketone body

DOI:  https://doi.org/10.1007/s11011-023-01288-2
medRxiv. 2023 Sep 26. pii: 2023.09.25.23296090. [Epub ahead of print]

Pharmacokinetic effects of a single-dose nutritional ketone ester supplement on brain ketone and glucose metabolism in alcohol use disorder - a pilot study.

Xinyi Li, Anthony J Young, Lais S Pereira-Rufino, Zhenhao Shi, Juliana Byanyima, Sianneh Vesslee, Rishika Reddy, Timothy Pond, Mark Elliott, Ravinder Reddy, Robert K Doot, Jan-Willem van der Veen, Henry R Kranzler, Ravi Prakash Reddy Nanga, Jacob G Dubroff, Corinde E Wiers.

Introduction: Acute alcohol intake decreases brain glucose metabolism and increases brain uptake of acetate, a metabolite of alcohol. Individuals with alcohol use disorder (AUD) show elevated brain acetate metabolism at the expense of glucose, a shift in energy utilization that persists beyond acute intoxication. We recently reported that nutritional ketosis and administration of ketone bodies as an alternative energy source to glucose reduce alcohol withdrawal severity and alcohol craving in AUD. However, the regional effects of nutritional ketosis on brain ketone (beta-hydroxybutyrate [BHB]) and glucose metabolism have not been studied in AUD.
Methods: Five participants with AUD underwent two magnetic resonance imaging (MRI) sessions and 4 participants with AUD underwent two positron emission tomography (PET) sessions with 18 F-fluorodeoxyglucose. All participants completed one session without KE intervention and one session during which they consumed 395 mg/kg (R) -3-hydroxybutyl (R) -3-hydroxybutyrate Ketone Ester (KE) intervention (TdeltaS Global Inc.) before the scan. The order of the sessions was randomized. For the PET cohort, blood glucose and ketone levels were assessed and voxel-wise maps of the cerebral metabolic rate of glucose (CMRglc) were computed at each session. For the MRI cohort, brain anterior cingulate BHB levels were assessed using magnetic resonance spectroscopy.
Results: A single dose of KE elevated blood BHB and anterior cingulate BHB levels compared to baseline. Moreover, blood glucose levels were lower with KE than baseline, and whole-brain CMRglc decreased by 17%. The largest KE-induced CMRglc reductions were in the frontal, occipital, cortex, and anterior cingulate cortices.
Conclusion: These findings provide preliminary evidence that KE administration elevates ketone and reduces brain glucose metabolism in humans, consistent with a shift from glucose to ketones as a brain energy source. Average reductions in CMRglc of 17% are similar to global average reductions documented with administration of 0.25-0.5 g/kg of alcohol. Documenting the clinical and neurometabolic effects of nutritional ketosis will yield fundamental knowledge as to its potential beneficial effects as a treatment for AUD and its underlying neural mechanisms.

DOI: https://doi.org/10.1101/2023.09.25.23296090
Nutrients. 2023 Oct 01. pii: 4244. [Epub ahead of print]15(19):

Supplementation of Medium-Chain Triglycerides Combined with Docosahexaenoic Acid Inhibits Amyloid Beta Protein Deposition by Improving Brain Glucose Metabolism in APP/PS1 Mice.

Zehao Wang, Dalong Zhang, Cheng Cheng, Zhenzhen Lin, Dezheng Zhou, Yue Sun, Wen Li, Jing Yan, Suhui Luo, Zhiyong Qian, Zhenshu Li, Guowei Huang.

  The deterioration of brain glucose metabolism predates the clinical onset of Alzheimer's disease (AD). Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA) positively improve brain glucose metabolism and decrease the expression of AD-related proteins. However, the effects of the combined intervention are unclear. The present study explored the effects of the supplementation of MCTs combined with DHA in improving brain glucose metabolism and decreasing AD-related protein expression levels in APP/PS1 mice. The mice were assigned into four dietary treatment groups: the control group, MCTs group, DHA group, and MCTs + DHA group. The corresponding diet of the respective groups was fed to mice from the age of 3 to 11 months. The results showed that the supplementation of MCTs combined with DHA could increase serum octanoic acid (C8:0), decanoic acid (C10:0), DHA, and β-hydroxybutyrate (β-HB) levels; improve glucose metabolism; and reduce nerve cell apoptosis in the brain. Moreover, it also aided with decreasing the expression levels of amyloid beta protein (Aβ), amyloid precursor protein (APP), β-site APP cleaving enzyme-1 (BACE1), and presenilin-1 (PS1) in the brain. Furthermore, the supplementation of MCTs + DHA was significantly more beneficial than that of MCTs or DHA alone. In conclusion, the supplementation of MCTs combined with DHA could improve energy metabolism in the brain of APP/PS1 mice, thus decreasing nerve cell apoptosis and inhibiting the expression of Aβ.

Keywords:  18F-FDG-PET-CT; APP/PS1 mouse; Alzheimer’s disease; amyloid beta protein; docosahexaenoic acid; glucose metabolism; medium-chain triglycerides

DOI:  https://doi.org/10.3390/nu15194244
Trends Cell Biol. 2023 Oct 05. pii: S0962-8924(23)00196-4. [Epub ahead of print]

The cell biology of APOE in the brain.

Ian A Windham, Sarah Cohen.

  Apolipoprotein E (APOE) traffics lipids in the central nervous system. The E4 variant of APOE is a major genetic risk factor for Alzheimer's disease (AD) and a multitude of other neurodegenerative diseases, yet the molecular mechanisms by which APOE4 drives disease are still unclear. A growing collection of studies in iPSC models, knock-in mice, and human postmortem brain tissue have demonstrated that APOE4 expression in astrocytes and microglia is associated with the accumulation of cytoplasmic lipid droplets, defects in endolysosomal trafficking, impaired mitochondrial metabolism, upregulation of innate immune pathways, and a transition into a reactive state. In this review, we collate these developments and suggest testable mechanistic hypotheses that could explain common APOE4 phenotypes.

Keywords:  Alzheimer’s disease; apolipoprotein E; astrocytes; lipid droplets; lipoproteins; microglia

DOI:  https://doi.org/10.1016/j.tcb.2023.09.004
Discov Med. 2023 Oct;35(178): 653-663

Role of Mitochondrial Dysfunction in Cellular Lipid Homeostasis and Disease.

Siresha Bathina, Undurti N Das.

  Mitochondria-associated membranes (MAMs) play a significant role in multiple cellular processes including lipid metabolism and neuronal survival. Fatty acids constitute 80% of the dry mass of the brain and are vital for life. Apart from mitochondrial β-oxidation, fatty acids are metabolized in part by peroxisomes to regulate the generation of acyl Coenzyme A and adenosine triphosphate (ATP). Ablation of mitochondria and its associated genes tether endoplasmic reticulum (ER)-Mitochondria contact and results in loss of function leading to aberrant lipid metabolism. Additionally, an increase in reactive oxygen species (ROS) levels along with free radicals' generation may lead to alteration in the integrity of membrane phospholipids, proteins, and DNA. Hence, it is critical to understand the effect of structural and functional aspects of mitochondria on lipid homeostasis. This review explains the role of mitochondrial dysfunction in lipid metabolism and its impact on various neurodegenerative diseases and metabolic disorders.

Keywords:  lipid metabolism; mitochondria dysfunction; neurodegenerative disease

DOI:  https://doi.org/10.24976/Discov.Med.202335178.64
Cell Rep. 2023 Oct 10. pii: S2211-1247(23)01253-6. [Epub ahead of print]42(10): 113241

Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.

Makayla S Lancaster, Byungwook Kim, Emma H Doud, Mason D Tate, Ahmad D Sharify, Hongyu Gao, Duojiao Chen, Ed Simpson, Patrick Gillespie, Xiaona Chu, Marcus J Miller, Yue Wang, Yunlong Liu, Amber L Mosley, Jungsu Kim, Brett H Graham.

  Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency.

Keywords:  ATAC sequencing; CP: Metabolism; CP: Neuroscience; RNA sequencing; chromatin; electron transport chain; mass spectrometry; metabolism; neurons; post-translational modification; succinyl-CoA synthetase; succinylation

DOI:  https://doi.org/10.1016/j.celrep.2023.113241
Proc Natl Acad Sci U S A. 2023 Oct 17. 120(42): e2302780120

Impairment of serine transport across the blood-brain barrier by deletion of Slc38a5 causes developmental delay and motor dysfunction.

Inna Radzishevsky, Maali Odeh, Oded Bodner, Salman Zubedat, Lihi Shaulov, Maxim Litvak, Kayoko Esaki, Takeo Yoshikawa, Bella Agranovich, Wen-Hong Li, Alex Radzishevsky, Eyal Gottlieb, Avi Avital, Herman Wolosker.

  Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. Slc38a5-KO pups exhibit motor impairments that are affected by the administration of L-serine at concentrations that replenish the serine pool in the brain. Our results highlight a critical role of Slc38a5 in supplying L-serine via the BBB for proper brain development.

Keywords:  D-serine; deoxysphingolipids; serine metabolism; synaptopathy

DOI:  https://doi.org/10.1073/pnas.2302780120
bioRxiv. 2023 Sep 26. pii: 2023.09.25.559216. [Epub ahead of print]

Pro-resolution lipid mediator maresin-1 ameliorates inflammation, promotes neuroprotection, and prevents disease progression in experimental models of multiple sclerosis.

Insha Zahoor, Mohammad Nematullah, Mohammad Ejaz Ahmed, Mena Fatma, Sajad Mir, Kamesh Ayasolla, Mirela Cerghet, Suresh Palaniyandi, Yang Mao-Draayer, Ramandeep Rattan, Shailendra Giri.

Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease in young adults, resulting in neurological defects and disability. The endogenous mechanisms to resolve inflammation are intact but become defective in patients, resulting in lack of resolution mediators and unresolved chronic inflammation. Docosahexaenoic acid (DHA) metabolism being impaired in MS, we hypothesize that supplementing its downstream metabolite maresin 1 (MaR1) will alleviate inflammation and demyelination in preclinical mouse model of MS; experimental allergic encephalomyelitis (EAE). Restoration of MaR1 by its exogenous administration in EAE mice propagated inflammatory resolution and had a protective effect on neurological deficits, prevented disease progression, and reduced disease severity by reducing immune cell infiltration (CD4+IL17+ and CD4+IFN-γ+) into the CNS. It significantly reduced the proinflammatory cytokine IL17 and promoted an anti-inflammatory response via IL10 and IL4. Neutralization of IL10 abolished the protective effect of MaR1 in EAE confirming IL10 is mediating MaR1 effect in EAE. Furthermore, it improved the pathophysiology and exerted neuroprotective effects by mitigating disease signs in EAE as evidenced by lower levels of NFL in the plasma of treated group compared to control and higher MBP expression in the brain from the MaR1 treated mice, decreased inflammatory infiltrates, and less demyelination and vacuolization in the spinal cord tissue sections of treated mice. SCENITH data confirmed that MaR1 maintains myelin by regulating oligodendrocyte metabolism. Also, it induces metabolic reprogramming in infiltrating CD4 cells and macrophages, which modulate their phenotype. Metabolic changes induced macrophages by MaR1 restores the impaired efferocytosis in EAE, promoting clearance of damaged myelin and dead cells; thereby lowering the disability with disease course. Overall, MaR1 supplementation has anti-inflammatory and neuroprotective effects in preclinical animal models and induces metabolic reprogramming in disease associated cell-types, promotes efferocytosis, implying that it could be a new therapeutic molecule in MS and other autoimmune diseases.
Highlights: Inflammation is dysregulated in EAE due to impaired synthesis of DHA derived proresolving lipid mediator MaR1.Administration of the resolution agonist MaR1 propagates resolution processes and improves neurological outcome in RR model of EAE.MaR1 ameliorates clinical signs of EAE by attenuating pro-inflammatory cytokine IL17 mediated response and promoting anti-inflammatory response through IL10.MaR1 supplementation improves the pathophysiology in EAE and shows neuroprotection as indicated by the lower levels of NFL in the plasma and higher expression of MBP in the brain of treated mice.MaR1 induces metabolic reprogramming in disease-associated cell types.MaR1 promotes efferocytosis in EAE through metabolic reprogramming of macrophages.
Significance: Inflammatory process is a protective response to several challenges like injury or infection. However, it must resolve over time to maintain tissue homeostasis. Impaired or delayed resolution leads to damaging effects, including chronic inflammation, tissue damage, and disease progression as occurs in multiple sclerosis (MS). We report that inflammation is dysregulated in preclinical animal model of MS, experimental autoimmune encephalomyelitis (EAE), partially due to impaired synthesis of proresolving lipid mediators. We show that the administration of the resolution agonist known as maresin 1 (MaR1) in EAE actively propagates resolution processes and improves neurological outcome. We conclude that MaR1 is a potential interventional candidate to attenuate dysregulated inflammation and to restore neurological deficits in EAE.
Graphical abstract:

DOI: https://doi.org/10.1101/2023.09.25.559216
bioRxiv. 2023 Sep 29. pii: 2023.09.29.559526. [Epub ahead of print]

Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging.

Dylan C Souder, Eric R McGregor, Timothy W Rhoads, Josef P Clark, Tiaira J Porter, Kevin Eliceiri, Darcie L Moore, Luigi Puglielli, Rozalyn M Anderson.

The brain is a high energy tissue, and the cell types of which it is comprised are distinct in function and in metabolic requirements. The transcriptional co-activator PGC-1a is a master regulator of mitochondrial function and is highly expressed in the brain; however, its cell-type specific role in regulating metabolism has not been well established. Here, we show that PGC-1a is responsive to aging and that expression of the neuron specific PGC-1a isoform allows for specialization in metabolic adaptation. Transcriptional profiles of the cortex from male mice show an impact of age on immune, inflammatory, and neuronal functional pathways and a highly integrated metabolic response that is associated with decreased expression of PGC-1a. Proteomic analysis confirms age-related changes in metabolism and further shows changes in ribosomal and RNA splicing pathways. We show that neurons express a specialized PGC-1a isoform that becomes active during differentiation from stem cells and is further induced during the maturation of isolated neurons. Neuronal but not astrocyte PGC-1a responds robustly to inhibition of the growth sensitive kinase GSK3b, where the brain specific promoter driven dominant isoform is repressed. The GSK3b inhibitor lithium broadly reprograms metabolism and growth signaling, including significantly lower expression of mitochondrial and ribosomal pathway genes and suppression of growth signaling, which are linked to changes in mitochondrial function and neuronal outgrowth. In vivo, lithium treatment significantly changes the expression of genes involved in cortical growth, endocrine, and circadian pathways. These data place the GSK3b/PGC-1a axis centrally in a growth and metabolism network that is directly relevant to brain aging.

DOI: https://doi.org/10.1101/2023.09.29.559526
Development. 2023 Oct 12. pii: dev.201930. [Epub ahead of print]

Calcium signals tune AMPK activity and mitochondrial homeostasis in dendrites of developing neurons.

Akane Hatsuda, Junko Kurisu, Kazuto Fujishima, Ayano Kawaguchi, Nobuhiko Ohno, Mineko Kengaku.

  Dendritic outgrowth in immature neurons is enhanced by neuronal activity and is considered one of the mechanisms of neural circuit optimization. It is known that calcium signals affect transcriptional regulation and cytoskeletal remodeling necessary for dendritic outgrowth. Here we demonstrate that activity-dependent calcium signaling also controls mitochondrial homeostasis via AMP-activated protein kinase (AMPK) in growing dendrites of differentiating hippocampal neurons. We found that the inhibition of neuronal activity induces dendritic hypotrophy with abnormally elongated mitochondria. In growing dendrites, AMPK is activated by neuronal activity and dynamically oscillates in synchrony with calcium spikes, and this AMPK oscillation is inhibited by CaMKK2 knockdown. AMPK activation leads to phosphorylation of MFF and ULK1, which initiate mitochondrial fission and mitophagy, respectively. Dendritic mitochondria in AMPK-depleted neurons exhibit impaired fission and mitophagy and display multiple signs of dysfunction. Genetic inhibition of fission leads to dendritic hypoplasia reminiscent of AMPK deficient neurons. Thus, AMPK activity is finely tuned by the calcium-CaMKK2 pathway and regulates mitochondrial homeostasis by facilitating removal of damaged components of mitochondria in growing neurons during normal brain development.

Keywords:  AMPK; Dendritogenesis; Hippocampal neurons; Mitochondria; Neuronal activity

DOI:  https://doi.org/10.1242/dev.201930
Dis Model Mech. 2023 Oct 01. pii: dmm050206. [Epub ahead of print]16(10):

Glycosphingolipids are linked to elevated neurotransmission and neurodegeneration in a Drosophila model of Niemann Pick type C.

Anna E Eberwein, Swarat S Kulkarni, Emma Rushton, Kendal Broadie.

  The lipid storage disease Niemann Pick type C (NPC) causes neurodegeneration owing primarily to loss of NPC1. Here, we employed a Drosophila model to test links between glycosphingolipids, neurotransmission and neurodegeneration. We found that Npc1a nulls had elevated neurotransmission at the glutamatergic neuromuscular junction (NMJ), which was phenocopied in brainiac (brn) mutants, impairing mannosyl glucosylceramide (MacCer) glycosylation. Npc1a; brn double mutants had the same elevated synaptic transmission, suggesting that Npc1a and brn function within the same pathway. Glucosylceramide (GlcCer) synthase inhibition with miglustat prevented elevated neurotransmission in Npc1a and brn mutants, further suggesting epistasis. Synaptic MacCer did not accumulate in the NPC model, but GlcCer levels were increased, suggesting that GlcCer is responsible for the elevated synaptic transmission. Null Npc1a mutants had heightened neurodegeneration, but no significant motor neuron or glial cell death, indicating that dying cells are interneurons and that elevated neurotransmission precedes neurodegeneration. Glycosphingolipid synthesis mutants also had greatly heightened neurodegeneration, with similar neurodegeneration in Npc1a; brn double mutants, again suggesting that Npc1a and brn function in the same pathway. These findings indicate causal links between glycosphingolipid-dependent neurotransmission and neurodegeneration in this NPC disease model.

Keywords:  Excitotoxicity; Glucosylceramide; Lipid storage disease; Mannosyl glucosylceramide; Neurotransmission

DOI:  https://doi.org/10.1242/dmm.050206
Cell Rep. 2023 Oct 02. pii: S2211-1247(23)01207-X. [Epub ahead of print] 113195

Very-long-chain fatty acids are crucial to neuronal polarity by providing sphingolipids to lipid rafts.

Atsuko Honda, Motohiro Nozumi, Yasuyuki Ito, Rie Natsume, Asami Kawasaki, Fubito Nakatsu, Manabu Abe, Haruki Uchino, Natsuki Matsushita, Kazutaka Ikeda, Makoto Arita, Kenji Sakimura, Michihiro Igarashi.

  Fatty acids have long been considered essential to brain development; however, the involvement of their synthesis in nervous system formation is unclear. We generate mice with knockout of GPSN2, an enzyme for synthesis of very-long-chain fatty acids (VLCFAs) and investigate the effects. Both GPSN2-/- and GPSN2+/- mice show abnormal neuronal networks as a result of impaired neuronal polarity determination. Lipidomics of GPSN2-/- embryos reveal that ceramide synthesis is specifically inhibited depending on FA length; namely, VLCFA-containing ceramide is reduced. We demonstrate that lipid rafts are highly enriched in growth cones and that GPSN2+/- neurons lose gangliosides in their membranes. Application of C24:0 ceramide, but not C16:0 ceramide or C24:0 phosphatidylcholine, to GPSN2+/- neurons rescues both neuronal polarity determination and lipid-raft density in the growth cone. Taken together, our results indicate that VLCFA synthesis contributes to physiological neuronal development in brain network formation, in particular neuronal polarity determination through the formation of lipid rafts.

Keywords:  CP: Cell biology; CP: Neuroscience

DOI:  https://doi.org/10.1016/j.celrep.2023.113195
Aging Dis. 2023 Sep 25.

Schizophrenia-Like Behaviors Arising from Dysregulated Proline Metabolism Are Associated with Altered Neuronal Morphology and Function in Mice with Hippocampal PRODH Deficiency.

Yuxiao Yao, Chenchen Jin, Yilie Liao, Xiang Huang, Ziying Wei, Yahong Zhang, Dongwei Li, Huanxing Su, Weiping Han, Dajiang Qin.

Despite decades of research being conducted to understand what physiological deficits in the brain are an underlying basis of psychiatric diseases like schizophrenia, it has remained difficult to establish a direct causal relationship between neuronal dysfunction and specific behavioral phenotypes. Moreover, it remains unclear how metabolic processes, including amino acid metabolism, affect neuronal function and consequently modulate animal behaviors. PRODH, which catalyzes the first step of proline degradation, has been reported as a susceptibility gene for schizophrenia. It has consistently been shown that PRODH knockout mice exhibit schizophrenia-like behaviors. However, whether the loss of PRODH directly impacts neuronal function or whether such neuronal deficits are linked to schizophrenia-like behaviors has not yet been examined. Herein, we first ascertained that dysregulated proline metabolism in humans is associated with schizophrenia. We then found that PRODH was highly expressed in the oreins layer of the mouse dorsal hippocampus. By using AAV- mediated shRNA, we depleted PRODH expression in the mouse dorsal hippocampus and subsequently observed hyperactivity and impairments in the social behaviors, learning, and memory of these mice. Furthermore, the loss of PRODH led to altered neuronal morphology and function both in vivo and in vitro. Our study demonstrates that schizophrenia-like behaviors may arise from dysregulated proline metabolism due to the loss of PRODH and are associated with altered neuronal morphology and function in mice.

DOI: https://doi.org/10.14336/AD.2023.0902
Radiol Case Rep. 2023 Dec;18(12): 4331-4337

Guanidinoacetate N-methyltransferase deficiency: Case report and brief review of the literature.

Joshua L Libell, Dhairya A Lakhani, Aneri B Balar, Musharaf Khan, Jeffrey S Carpenter, Joe T Joseph.

  Guanidinoacetate N-methyltransferase (GAMT) deficiency is a rare autosomal recessive disorder characterized by a decrease in creatine synthesis, resulting in cerebral creatine deficiency syndrome (CCDS). GAMT deficiency is caused by mutations in the GAMT gene located on chromosome 19, which impairs the conversion of guanidinoacetic acid (GAA) to creatine. The resulting accumulation of the toxic metabolite GAA and the lack of creatine lead to various symptoms, including global developmental delays, behavioral issues, and epilepsy. The gold standard for diagnosis of GAMT deficiency is genetic testing. Treatment options for GAMT deficiency include creatine supplementation, ornithine supplementation, arginine restriction, and sodium benzoate supplementation. These treatment options have been shown to improve movement disorders and epileptic symptoms, but their impact on intellectual and speech development is limited. Early intervention has shown promising results in normalizing neurological development in a minor subgroup of patients. Therefore, there is a growing need for newborn screening techniques to detect GAMT deficiency early and prevent permanent neurological delays. Here we report a case of GAMT deficiency with emphasis on imaging presentation. Our case showed reduced brain parenchyma creatine stores on MR Spectroscopy, which may provide an avenue to aid in early diagnosis.

Keywords:  Cerebral creatine deficiency syndrome; Creatine; Genetic testing; Global developmental delay; Guanidinoacetate N-Methyltransferase; Magnetic resonance spectroscopy

DOI:  https://doi.org/10.1016/j.radcr.2023.09.026
Glob Med Genet. 2023 Dec;10(4): 278-281

The First Reported Case of a Child with Two Different Rare Metabolic Disorders: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency and Encephalomyopathic Mitochondrial DNA Depletion Syndrome 13.

Maha Alotaibi, Amal Alqasmi, Faisal Albassam, Turki Alkahtani, Muath Alqahtany, Mohammed Alkhaldi.

  One of the most common inborn errors in fatty acid β oxidation (FAO) is a very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency. It is autosomal recessive. The enzyme used in the first phase of FAO is VLCAD. The enzyme is responsible for β oxidation spiral pathway's initial step, the dehydrogenation process of long-chain fatty acyl-CoA. The phenotypes include hypoglycemia, hepatomegaly, cardiomyopathy, and occasionally abrupt mortality. Most VLCAD deficiencies in newborns are now detected during the neonatal period due to the development of newborn screening programs. Mitochondrial DNA depletion syndromes (MTDPS) are one of the rarest metabolic disorders. It is an autosomal recessive disease caused by defects in genes necessary for the maintenance of mitochondrial DNA (mtDNA). One of these FBXL4 (F-box and leucine-rich repeat protein 4) variants causes encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), which presents as a failure to thrive, severe global developmental delay, hypotonia, early infantile onset of encephalopathy, and lactic acidosis. We report here the case of a Saudi infant born to consanguineous parents who presented to us with severe failure to thrive, profound neurodevelopmental delays, and facial dysmorphic features. Whole-exome sequencing (WES) showed the infants had MTDPS13. The FBXL4 variant c.1698A > G p. (Ile566Met) has previously been described as a disease that causes developmental delay and lactic acidosis, and another variant has also been detected in the patient. The ACADVL variant c.134C > A p. (Ser45*) has previously been described to cause VLCAD deficiency. A comprehensive literature review showed our patient to be the first case of MTDPS13 and VLCAD reported to date worldwide.

Keywords:  FBXL4; hypoglycemia; mitochondrial DNA; mitochondrial diseases; pediatric genetics; very long-chain acyl-CoA dehydrogenase deficiency

DOI:  https://doi.org/10.1055/s-0043-1775979
J Lipid Res. 2023 Oct 10. pii: S0022-2275(23)00113-X. [Epub ahead of print]64(10): 100440

Metabolic switch from glycogen to lipid in the liver maintains glucose homeostasis in neonatal mice.

Liangkui Li, Haoyu Zhou, Jinhui Wang, Jiaxin Li, Xuchao Lyu, Wenshan Wang, Chengting Luo, He Huang, Dawang Zhou, Xiaowei Chen, Li Xu, Peng Li.

  Neonates strive to acquire energy when the continuous transplacental nutrient supply ceases at birth, whereas milk consumption takes hours to start. Using murine models, we report the metabolic switches in the first days of life, with an unexpected discovery of glucose as the universal fuel essential for neonatal life. Blood glucose quickly drops as soon as birth, but immediately rebounds even before suckling and maintains stable afterward. Meanwhile, neonatal liver undergoes drastic metabolic changes, from extensive glycogenolysis before suckling to dramatically induced fatty acid oxidation (FAO) and gluconeogenesis after milk suckling. Unexpectedly, blocking hepatic glycogenolysis only caused a transient hypoglycemia before milk suckling without causing lethality. Limiting lipid supply in milk (low-fat milk, [LFM]) using Cidea-/- mice, however, led to a chronic and severe hypoglycemia and consequently claimed neonatal lives. While fat replenishment rescued LFM-caused neonatal lethality, the rescue effects were abolished by blocking FAO or gluconeogenesis, pointing to a funneling of lipids and downstream metabolites into glucose as the essential fuel. Finally, glucose administration also rescued LFM-caused neonatal lethality, independent on FAO or gluconeogenesis. Therefore, our results show that the liver works as an energy conversion center to maintain blood glucose homeostasis in neonates, providing theoretical basis for managing infant hypoglycemia.

Keywords:  Physiology; biological sciences; gluconeogenesis; glucose homeostasis; glycogen; lipids; neonates

DOI:  https://doi.org/10.1016/j.jlr.2023.100440
Exp Neurol. 2023 Oct 06. pii: S0014-4886(23)00249-2. [Epub ahead of print]370 114564

Inhibition of the proteoglycan receptor PTPσ promotes functional recovery on a rodent model of preterm hypoxic-ischemic brain injury.

Ran Wang, Tiantian Li, Sihao Diao, Chao Chen.

   BACKGROUND: Preterm white matter injury (WMI) is the most common brain injury in preterm infants and is associated with long-term adverse neurodevelopmental outcomes. Protein tyrosine phosphatase sigma (PTPσ) was discovered as chondroitin sulfate proteoglycan (CSPG) receptor that played roles in inhibiting myelin regeneration in spinal injury, experimental autoimmune encephalomyelitis, and stroke models. However, the role of PTPσ in perinatal WMI is not well understood.
AIMS: This study examines the effect of PTPσ inhibition on neurodevelopmental outcomes, myelination, and neuroinflammation in a mouse model of preterm WMI.
MATERIALS AND METHODS: Modified Rice-Vannucci model was performed on postnatal day 3 (P3) C57BL/6 mice. Intracellular Sigma Peptide (ISP) or vehicle was administrated subcutaneously one hour after injury for an additional 14 consecutive days. A battery of behavioral tests was performed to evaluate the short- and long-term effects of ISP on neurobehavioral deficit. Real time qPCR, western blot, immunofluorescence, and transmission electron microscopy were performed to assess white matter development. qPCR and flow cytometry were performed to evaluate neuroinflammation and microglia/macrophage phenotype.
RESULTS: The expression of PTPσ was increased after preterm WMI. ISP improved short-term neurological outcomes and ameliorated long-term motor and cognitive function of mice after preterm WMI. ISP promoted oligodendrocyte differentiation, maturation, myelination, and improved microstructure of myelin after preterm WMI. Furthermore, ISP administration fostered a beneficial inflammatory response in the acute phase after preterm WMI, inhibited the infiltration of peripheral macrophages, and promoted anti-inflammatory phenotype of microglia/macrophages.
CONCLUSION: PTPσ inhibition can ameliorate neurofunctional deficit, promote white matter development, modulate neuroinflammation and microglia/macrophage phenotype after preterm WMI. Thus, ISP administration may be a potential therapeutic strategy to improve neurodevelopmental outcomes of perinatal WMI.

Keywords:  Myelination; Neurodevelopmental outcomes; Neuroinflammation; Preterm white matter injury; Protein tyrosine phosphatase sigma

DOI:  https://doi.org/10.1016/j.expneurol.2023.114564
Int J Mol Sci. 2023 Oct 03. pii: 14857. [Epub ahead of print]24(19):

The Physiological and Pathological Role of Acyl-CoA Oxidation.

Sylwia Szrok-Jurga, Aleksandra Czumaj, Jacek Turyn, Areta Hebanowska, Julian Swierczynski, Tomasz Sledzinski, Ewa Stelmanska.

  Fatty acid metabolism, including β-oxidation (βOX), plays an important role in human physiology and pathology. βOX is an essential process in the energy metabolism of most human cells. Moreover, βOX is also the source of acetyl-CoA, the substrate for (a) ketone bodies synthesis, (b) cholesterol synthesis, (c) phase II detoxication, (d) protein acetylation, and (d) the synthesis of many other compounds, including N-acetylglutamate-an important regulator of urea synthesis. This review describes the current knowledge on the importance of the mitochondrial and peroxisomal βOX in various organs, including the liver, heart, kidney, lung, gastrointestinal tract, peripheral white blood cells, and other cells. In addition, the diseases associated with a disturbance of fatty acid oxidation (FAO) in the liver, heart, kidney, lung, alimentary tract, and other organs or cells are presented. Special attention was paid to abnormalities of FAO in cancer cells and the diseases caused by mutations in gene-encoding enzymes involved in FAO. Finally, issues related to α- and ω- fatty acid oxidation are discussed.

Keywords:  acyl-CoA; beta-oxidation; fatty acid metabolism; peroxisomal fatty acid oxidation

DOI:  https://doi.org/10.3390/ijms241914857
iScience. 2023 Oct 20. 26(10): 107913

mNSCs overexpressing Rimkla transplantation facilitates cognitive recovery in a mouse model of traumatic brain injury.

Tongjie Ji, Ying Pang, Meng Cheng, Rui Wang, Xu Chen, Chunyu Zhang, Min Liu, Jing Zhang, Chunlong Zhong.

  N-acetyl aspartyl-glutamate (NAAG) is easily inactivated for the hydrolysis of NAAG peptidase on the surface of glial cells, thereby losing its endogenous neuroprotective effect after traumatic brain injury. In this study, lentiviral vectors were used to over express/knock out NAAG synthetase II (Rimkla) in mouse embryonic neural stem cells (mNSCs) in vitro and these mNSCs were transplanted at the lesion site in a mouse model of controlled cortical impact (CCI). In vivo experiments showed that transplantation of mNSCs overexpressing Rimkla regulated glutamate-glutamine cycling between adjacent astrocytes and neurons in the subacute phase of CCI, thereby enhancing support for neuronal metabolism and promoting neuronal synaptic repair in the hippocampal CA3 region. Taken together, these findings demonstrate that transplantation of neural stem cells overexpressing Rimkla can effectively increase the NAAG concentration in local brain regions, which opens up new ideas for the maintenance of NAAG neuroprotective effects after TBI.

Keywords:  Cell biology; Clinical neuroscience; Neurosurgery

DOI:  https://doi.org/10.1016/j.isci.2023.107913
J Lipid Res. 2023 Oct 11. pii: S0022-2275(23)00130-X. [Epub ahead of print] 100457

Cooperative lipolytic control of neuronal triacylglycerol by spastic paraplegia-associated enzyme DDHD2 and ATGL.

Peter Hofer, Gernot F Grabner, Mario König, Hao Xie, Dominik Bulfon, Anton E Ludwig, Heimo Wolinski, Robert Zimmermann, Rudolf Zechner, Christoph Heier.

  Intracellular lipolysis - the enzymatic breakdown of lipid droplet (LD)-associated triacylglycerols (TAGs) - depends on the cooperative action of several hydrolytic enzymes and regulatory proteins, together designated as lipolysome. Adipose triglyceride lipase (ATGL) acts as a major cellular TAG hydrolase and core effector of the lipolysome in many peripheral tissues. Neurons initiate lipolysis independent of ATGL via DDHD domain-containing 2 (DDHD2), a multifunctional lipid hydrolase whose dysfunction causes neuronal TAG deposition and hereditary spastic paraplegia. Whether and how DDHD2 cooperates with other lipolytic enzymes is currently unknown. In this study we further investigated the enzymatic properties and functions of DDHD2 in neuroblastoma cells and primary neurons. We found that DDHD2 hydrolyzes multiple acylglycerols in vitro and substantially contributes to neutral lipid hydrolase activities of neuroblastoma cells and brain tissue. Substrate promiscuity of DDHD2 allowed its engagement at different steps of the lipolytic cascade: In neuroblastoma cells, DDHD2 functioned exclusively downstream of ATGL in the hydrolysis of sn-1,3-diacylglycerol (DAG) isomers but was dispensable for TAG hydrolysis and LD homeostasis. In primary cortical neurons, DDHD2 exhibited lipolytic control over both, DAG and TAG, and complemented ATGL-dependent TAG hydrolysis. We conclude that neuronal cells use non-canonical configurations of the lipolysome and engage DDHD2 as dual TAG/DAG hydrolase in cooperation with ATGL.

Keywords:  Lipolysis and fatty acid metabolism; brain lipids; enzymology; lipase; lipid droplets; neurons; spastic paraplegia; triacylglycerol

DOI:  https://doi.org/10.1016/j.jlr.2023.100457
Pharmacol Res. 2023 Oct 05. pii: S1043-6618(23)00308-0. [Epub ahead of print]197 106952

Possible role of tryptophan metabolism along the microbiota-gut-brain axis on cognitive & behavioral aspects in Phenylketonuria.

SIMMESN Working Group for Gut Microbiota in Inborn Errors of Metabolism

  Cognitive and psychiatric disorders are well documented across the lifetime of patients with inborn errors of metabolism (IEMs). Gut microbiota impacts behavior and cognitive functions through the gut-brain axis (GBA). According to recent research, a broad spectrum of GBA disorders may be influenced by a perturbed Tryptophan (Trp) metabolism and are associated with alterations in composition or function of the gut microbiota. Furthermore, early-life diets may influence children's neurodevelopment and cognitive deficits in adulthood. In Phenylketonuria (PKU), since the main therapeutic intervention is based on a life-long restrictive diet, important alterations of gut microbiota have been observed. Studies on PKU highlight the impact of alterations of gut microbiota on the central nervous system (CNS), also investigating the involvement of metabolic pathways, such as Trp and kynurenine (KYN) metabolisms, involved in numerous neurodegenerative disorders. An alteration of Trp metabolism with an imbalance of the KYN pathway towards the production of neurotoxic metabolites implicated in numerous neurodegenerative and inflammatory diseases has been observed in PKU patients supplemented with Phe-free amino acid medical foods (AA-MF). The present review investigates the possible link between gut microbiota and the brain in IEMs, focusing on Trp metabolism in PKU. Considering the evidence collected, cognitive and behavioral well-being should always be monitored in routine IEMs clinical management. Further studies are required to evaluate the possible impact of Trp metabolism, through gut microbiota, on cognitive and behavioral functions in IEMs, to identify innovative dietetic strategies and improve quality of life and mental health of these patients.

Keywords:  Cognitive-behavioral development; Inborn errors metabolism; Kynurenine; Microbiota-gut-brain axis; Phenylketonuria; Tryptophan metabolism

DOI:  https://doi.org/10.1016/j.phrs.2023.106952
Front Neurosci. 2023 ;17 1191492

Isolation of the murine Glut1 deficient thalamocortical circuit: wavelet characterization and reverse glucose dependence of low and gamma frequency oscillations.

Elysandra M Solis, Levi B Good, Rafael Granja Vázquez, Sourav Patnaik, Ana G Hernandez-Reynoso, Qian Ma, Gustavo Angulo, Aksharkumar Dobariya, Stuart F Cogan, Joseph J Pancrazio, Juan M Pascual, Vikram Jakkamsetti.

  Glucose represents the principal brain energy source. Thus, not unexpectedly, genetic glucose transporter 1 (Glut1) deficiency (G1D) manifests with encephalopathy. G1D seizures, which constitute a prominent disease manifestation, often prove refractory to medications but may respond to therapeutic diets. These seizures are associated with aberrant thalamocortical oscillations as inferred from human electroencephalography and functional imaging. Mouse electrophysiological recordings indicate that inhibitory neuron failure in thalamus and cortex underlies these abnormalities. This provides the motivation to develop a neural circuit testbed to characterize the mechanisms of thalamocortical synchronization and the effects of known or novel interventions. To this end, we used mouse thalamocortical slices on multielectrode arrays and characterized spontaneous low frequency oscillations and less frequent 30-50 Hz or gamma oscillations under near-physiological bath glucose concentration. Using the cortical recordings from layer IV among other regions recorded, we quantified oscillation epochs via an automated wavelet-based algorithm. This method proved analytically superior to power spectral density, short-time Fourier transform or amplitude-threshold detection. As expected from human observations, increased bath glucose reduced the lower frequency oscillations while augmenting the gamma oscillations, likely reflecting strengthened inhibitory neuron activity, and thus decreasing the low:high frequency ratio (LHR). This approach provides an ex vivo method for the evaluation of mechanisms, fuels, and pharmacological agents in a crucial G1D epileptogenic circuit.

Keywords:  Glut1; glucose transporter; metabolism; multielectrode array; oscillations; thalamus

DOI:  https://doi.org/10.3389/fnins.2023.1191492