bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2023–01–08
thirteen papers selected by
Regina F. Fernández, Johns Hopkins University
  1. The impact of amino acid metabolism on adult neurogenesis.
  2. Glial Cell Metabolic Profile Upon Iron Deficiency: Oligodendroglial and Astroglial Casualties of Bioenergetic Adjustments.
  3. Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling.
  4. Loss of brain energy metabolism control as a driver for memory impairment upon insulin resistance.
  5. Lysophosphatidylcholines and phosphatidylcholines as biomarkers for stroke recovery.
  6. Brain histone beta-hydroxybutyrylation couples metabolism with gene expression.
  7. A new model for fatty acid hydroxylase-associated neurodegeneration reveals mitochondrial and autophagy abnormalities.
  8. Lathosterolosis: a rare cholesterol metabolism disorder with a wide range of clinical variability.
  9. Myelin lipid metabolism and its role in myelination and myelin maintenance.
  10. Dysregulated cholesterol metabolism, aberrant excitability and altered cell cycle of astrocytes in fragile X syndrome.
  11. Targeting fatty acid metabolism in glioblastoma.
  12. Dysregulated systemic metabolism in a Down syndrome mouse model.
  13. Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene.
  1. Biochem Soc Trans. 2023 Jan 06. pii: BST20220762. [Epub ahead of print]
    The impact of amino acid metabolism on adult neurogenesis.
    Ye Guo, Xing Luo, Weixiang Guo.
      Adult neurogenesis is a multistage process during which newborn neurons are generated through the activation and proliferation of neural stem cells (NSCs) and integrated into existing neural networks. Impaired adult neurogenesis has been observed in various neurological and psychiatric disorders, suggesting its critical role in cognitive function, brain homeostasis, and neural repair. Over the past decades, mounting evidence has identified a strong association between metabolic status and adult neurogenesis. Here, we aim to summarize how amino acids and their neuroactive metabolites affect adult neurogenesis. Furthermore, we discuss the causal link between amino acid metabolism, adult neurogenesis, and neurological diseases. Finally, we propose that systematic elucidation of how amino acid metabolism regulates adult neurogenesis has profound implications not only for understanding the biological underpinnings of brain development and neurological diseases, but also for providing potential therapeutic strategies to intervene in disease progression.
    Keywords:  adult neurogenesis; amino acid metabolism; arginine metabolism; one-carbon metabolism; tryptophan metabolism
    DOI:  https://doi.org/10.1042/BST20220762
  2. Mol Neurobiol. 2023 Jan 03.
    Glial Cell Metabolic Profile Upon Iron Deficiency: Oligodendroglial and Astroglial Casualties of Bioenergetic Adjustments.
    María Victoria Rosato-Siri, Pamela V Martino Adami, María Eugenia Guitart, Sandra Verstraeten, Laura Morelli, Jorge Correale, Juana María Pasquini.
      Iron deficiency (ID) represents one of the most prevalent nutritional deficits, affecting almost two billion people worldwide. Gestational iron deprivation induces hypomyelination due to oligodendroglial maturation deficiencies and is thus a useful experimental model to analyze oligodendrocyte (OLG) requirements to progress to a mature myelinating state. A previous proteomic study in the adult ID brain by our group demonstrated a pattern of dysregulated proteins involved in the tricarboxylic acid cycle and mitochondrial dysfunction. The aim of the present report was to assess bioenergetics metabolism in primary cultures of OLGs and astrocytes (ASTs) from control and ID newborns, on the hypothesis that the regulation of cell metabolism correlates with cell maturation. Oxygen consumption and extracellular acidification rates were measured using a Seahorse extracellular flux analyzer. ID OLGs and ASTs both exhibited decreased spare respiratory capacity, which indicates that ID effectively induces mitochondrial dysfunction. A decrease in glycogen granules was observed in ID ASTs, and an increase in ROS production was detected in ID OLGs. Immunolabeling of structural proteins showed that mitochondrial number and size were increased in ID OLGs, while an increased number of smaller mitochondria was observed in ID ASTs. These results reflect an unfavorable bioenergetic scenario in which ID OLGs fail to progress to a myelinating state, and indicate that the regulation of cell metabolism may impact cell fate decisions and maturation.
    Keywords:  Astrocytes; Bioenergetic parameters; Glial cell metabolism; Glycogen consumption; Iron deficiency; Mitochondrial dysfunction; Oligodendrocytes
    DOI:  https://doi.org/10.1007/s12035-022-03149-y
  3. Mol Psychiatry. 2023 Jan 06.
    Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling.
    Marie-Lise Jobin, Véronique De Smedt-Peyrusse, Fabien Ducrocq, Rim Baccouch, Asma Oummadi, Maria Hauge Pedersen, Brian Medel-Lacruz, Maria-Florencia Angelo, Sandrine Villette, Pierre Van Delft, Laetitia Fouillen, Sébastien Mongrand, Jana Selent, Tarson Tolentino-Cortez, Gabriel Barreda-Gómez, Stéphane Grégoire, Elodie Masson, Thierry Durroux, Jonathan A Javitch, Ramon Guixà-González, Isabel D Alves, Pierre Trifilieff.
      Increasing evidence supports a relationship between lipid metabolism and mental health. In particular, the biostatus of polyunsaturated fatty acids (PUFAs) correlates with some symptoms of psychiatric disorders, as well as the efficacy of pharmacological treatments. Recent findings highlight a direct association between brain PUFA levels and dopamine transmission, a major neuromodulatory system implicated in the etiology of psychiatric symptoms. However, the mechanisms underlying this relationship are still unknown. Here we demonstrate that membrane enrichment in the n-3 PUFA docosahexaenoic acid (DHA), potentiates ligand binding to the dopamine D2 receptor (D2R), suggesting that DHA acts as an allosteric modulator of this receptor. Molecular dynamics simulations confirm that DHA has a high preference for interaction with the D2R and show that membrane unsaturation selectively enhances the conformational dynamics of the receptor around its second intracellular loop. We find that membrane unsaturation spares G protein activity but potentiates the recruitment of β-arrestin in cells. Furthermore, in vivo n-3 PUFA deficiency blunts the behavioral effects of two D2R ligands, quinpirole and aripiprazole. These results highlight the importance of membrane unsaturation for D2R activity and provide a putative mechanism for the ability of PUFAs to enhance antipsychotic efficacy.
    DOI:  https://doi.org/10.1038/s41380-022-01928-6
  4. Biochem Soc Trans. 2023 Jan 06. pii: BST20220789. [Epub ahead of print]
    Loss of brain energy metabolism control as a driver for memory impairment upon insulin resistance.
    João M N Duarte.
      The pathophysiological mechanisms intersecting metabolic and neurodegenerative disorders include insulin resistance, which has a strong involvement of environmental factors. Besides central regulation of whole-body homeostasis, insulin in the central nervous system controls molecular signalling that is critical for cognitive performance, namely signalling through pathways that modulate synaptic transmission and plasticity, and metabolism in neurons and astrocytes. This review provides an overview on how insulin signalling in the brain might regulate brain energy metabolism, and further identified molecular mechanisms by which brain insulin resistance might impair synaptic fuelling, and lead to cognitive deterioration.
    Keywords:  bioenergetics; central nervous system; insulin resistance; metabolism; neuromodulation; type 2 diabetes
    DOI:  https://doi.org/10.1042/BST20220789
  5. Front Neurol. 2022 ;13 1047101
    Lysophosphatidylcholines and phosphatidylcholines as biomarkers for stroke recovery.
    Meiling Huang, Shaohang Xu, Mingchao Zhou, Jiao Luo, Fubing Zha, Linlin Shan, Qingqing Yang, Baojin Zhou, Yulong Wang.
      Stroke is a serious global public health issue, associated with severe disability and high mortality rates. Its early detection is challenging, and no effective biomarkers are available. To obtain a better understanding of stroke prevention, management, and recovery, we conducted lipidomic analyses to characterize plasma metabolic features. Lipid species were measured using an untargeted lipidomic analysis with liquid chromatography-tandem mass spectrometry. Sixty participants were recruited in this cohort study, including 20 healthy individuals and 40 patients with stroke. To investigate the association between lipids related to long-term functional recovery in stroke patients. The primary independent variable was activities of daily living (ADL) dependency upon admission to the stroke unit and at the 3-month follow-up appointment. ADL dependency was assessed using the Barthel Index. Eleven significantly altered lipid species between the stroke and healthy groups were detected and displayed in a hierarchically clustered heatmap. Acyl carnitine, triacylglycerol, and ceramides were detected as potential lipid markers. Regarding the association between lipid profiles and functional status of patients with stroke the results indicated, lysophosphatidylcholines (LPC) and phosphatidylcholines were closely associated with stroke recovery. LPC may contribute positively role in patient's rehabilitation process via an anti-inflammatory mechanism. Appropriate management or intervention for lipid levels is expected to lead to better clinical outcomes.
    Keywords:  biomarkers; lipidomics; lysophosphatidylcholines; mass spectrometry; stroke; stroke recovery
    DOI:  https://doi.org/10.3389/fneur.2022.1047101
  6. Cell Mol Life Sci. 2023 Jan 06. 80(1): 28
    Brain histone beta-hydroxybutyrylation couples metabolism with gene expression.
    Sara Cornuti, Siwei Chen, Leonardo Lupori, Francesco Finamore, Fabrizia Carli, Muntaha Samad, Simona Fenizia, Matteo Caldarelli, Francesca Damiani, Francesco Raimondi, Raffaele Mazziotti, Christophe Magnan, Silvia Rocchiccioli, Amalia Gastaldelli, Pierre Baldi, Paola Tognini.
      Little is known about the impact of metabolic stimuli on brain tissue at a molecular level. The ketone body beta-hydroxybutyrate (BHB) can be a signaling molecule regulating gene transcription. Thus, we assessed lysine beta-hydroxybutyrylation (K-bhb) levels in proteins extracted from the cerebral cortex of mice undergoing a ketogenic metabolic challenge (48 h fasting). We found that fasting enhanced K-bhb in a variety of proteins including histone H3. ChIP-seq experiments showed that K9 beta-hydroxybutyrylation of H3 (H3K9-bhb) was significantly enriched by fasting on more than 8000 DNA loci. Transcriptomic analysis showed that H3K9-bhb on enhancers and promoters correlated with active gene expression. One of the most enriched functional annotations both at the epigenetic and transcriptional level was "circadian rhythms''. Indeed, we found that the diurnal oscillation of specific transcripts was modulated by fasting at distinct zeitgeber times both in the cortex and suprachiasmatic nucleus. Moreover, specific changes in locomotor activity daily features were observed during re-feeding after 48-h fasting. Thus, our results suggest that fasting remarkably impinges on the cerebral cortex transcriptional and epigenetic landscape, and BHB acts as a powerful epigenetic molecule in the brain through direct and specific histone marks remodeling in neural tissue cells.
    Keywords:  Beta-hydroxybutyrylation; Cerebral cortex; Epigenome; Fasting; Transcriptome
    DOI:  https://doi.org/10.1007/s00018-022-04673-9
  7. Front Cell Dev Biol. 2022 ;10 1000553
    A new model for fatty acid hydroxylase-associated neurodegeneration reveals mitochondrial and autophagy abnormalities.
    Frida Mandik, Yuliia Kanana, Jost Rody, Sophie Misera, Bernd Wilken, Björn-Hergen Laabs von Holt, Christine Klein, Melissa Vos.
      Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a rare disease that exhibits brain modifications and motor dysfunctions in early childhood. The condition is caused by a homozygous or compound heterozygous mutation in fatty acid 2 hydroxylase (FA2H), whose encoded protein synthesizes 2-hydroxysphingolipids and 2-hydroxyglycosphingolipids and is therefore involved in sphingolipid metabolism. A few FAHN model organisms have already been established and give the first insight into symptomatic effects. However, they fail to establish the underlying cellular mechanism of FAHN so far. Drosophila is an excellent model for many neurodegenerative disorders; hence, here, we have characterized and validated the first FAHN Drosophila model. The investigation of loss of dfa2h lines revealed behavioral abnormalities, including motor impairment and flying disability, in addition to a shortened lifespan. Furthermore, alterations in mitochondrial dynamics, and autophagy were identified. Analyses of patient-derived fibroblasts, and rescue experiments with human FA2H, indicated that these defects are evolutionarily conserved. We thus present a FAHN Drosophila model organism that provides new insights into the cellular mechanism of FAHN.
    Keywords:  Drosophila melanogaster; FA2H; autophagy; fatty acid hydroxylase-associated neurodegeneration; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2022.1000553
  8. J Pediatr Endocrinol Metab. 2023 Jan 06.
    Lathosterolosis: a rare cholesterol metabolism disorder with a wide range of clinical variability.
    Elif Söbü, Gül Demet Kaya Özçora, Özlem Görükmez, Bahtiyar Şahinoğlu.
       OBJECTIVES: Lathosterolosis is a rare autosomal recessive congenital disease that occurs due to homozygous or compound heterozygous mutations in the sterol C5-desaturase (SC5D) gene. We report a male patient with biallelic missense variant detected in the SC5D gene.
    CASE PRESENTATION: An eight-month-old male patient was referred to the department of paediatric neurology for status epilepticus. He had no remarkable dysmorphic features except micrognathia, ptotic ear and thin-stranded hair. Laboratory tests revealed an alanine aminotransferase level of 502 IU/L and an aspartate aminotransferase level of 279 IU/L; other biochemical test results were normal. The brain MRI revealed atrophic changes in both hemispheres. A decrease in the volume of brain stem and thin corpus callosum were noticeable. Whole exome sequencing was performed because of consanguineous marriage and sibling death in his medical history, and the encountered features were consistent with suspected neurometabolic disease in the cranial imaging and the presence of borderline psychomotor retardation. A biallelic missense variant, c.656T>C p.(Leu219Ser), was identified in the SC5D gene.
    CONCLUSIONS: Lathosterolosis is a rare cholesterol metabolism disorder and can be presented with a wide range of clinical features by newly reported cases. Lathosterolosis should be considered in cases with cataracts, delayed neuromotor developmental milestones and high levels of liver enzymes.
    Keywords:  cholesterol metabolism; elevated transaminases; lathosterol; microcephaly
    DOI:  https://doi.org/10.1515/jpem-2022-0586
  9. Innovation (Camb). 2023 Jan 30. 4(1): 100360
    Myelin lipid metabolism and its role in myelination and myelin maintenance.
    Joseph A Barnes-Vélez, Fatma Betul Aksoy Yasar, Jian Hu.
      Myelin is a specialized cell membrane indispensable for rapid nerve conduction. The high abundance of membrane lipids is one of myelin's salient features that contribute to its unique role as an insulator that electrically isolates nerve fibers across their myelinated surface. The most abundant lipids in myelin include cholesterol, glycosphingolipids, and plasmalogens, each playing critical roles in myelin development as well as function. This review serves to summarize the role of lipid metabolism in myelination and myelin maintenance, as well as the molecular determinants of myelin lipid homeostasis, with an emphasis on findings from genetic models. In addition, the implications of myelin lipid dysmetabolism in human diseases are highlighted in the context of hereditary leukodystrophies and neuropathies as well as acquired disorders such as Alzheimer's disease.
    DOI:  https://doi.org/10.1016/j.xinn.2022.100360
  10. Glia. 2023 Jan 03.
    Dysregulated cholesterol metabolism, aberrant excitability and altered cell cycle of astrocytes in fragile X syndrome.
    Baiyan Ren, Maria Burkovetskaya, Yoosun Jung, Lara Bergdolt, Steven Totusek, Veronica Martinez-Cerdeno, Kelly Stauch, Zeljka Korade, Anna Dunaevsky.
      Fragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. While neuronal contribution to FXS has been extensively studied in both animal and human-based models of FXS, the roles of astrocytes, a type of glial cells in the brain, are largely unknown. Here, we generated a human-based FXS model via differentiation of astrocytes from human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) and characterized their development, function, and proteomic profiles. We identified shortened cell cycle, enhanced Ca2+ signaling, impaired sterol biosynthesis, and pervasive alterations in the proteome of FXS astrocytes. Our work identified astrocytic impairments that could contribute to the pathogenesis of FXS and highlight astrocytes as a novel therapeutic target for FXS treatment.
    DOI:  https://doi.org/10.1002/glia.24331
  11. J Clin Invest. 2023 Jan 03. pii: e163448. [Epub ahead of print]133(1):
    Targeting fatty acid metabolism in glioblastoma.
    Jason Miska, Navdeep S Chandel.
      Glioblastoma (GBM) is a primary tumor of the brain defined by its uniform lethality and resistance to conventional therapies. There have been considerable efforts to untangle the metabolic underpinnings of this disease to find novel therapeutic avenues for treatment. An emerging focus in this field is fatty acid (FA) metabolism, which is critical for numerous diverse biological processes involved in GBM pathogenesis. These processes can be classified into four broad fates: anabolism, catabolism, regulation of ferroptosis, and the generation of signaling molecules. Each fate provides a unique perspective by which we can inspect GBM biology and gives us a road map to understanding this complicated field. This Review discusses the basic, translational, and clinical insights into each of these fates to provide a contemporary understanding of FA biology in GBM. It is clear, based on the literature, that there are far more questions than answers in the field of FA metabolism in GBM, and substantial efforts should be made to untangle these complex processes in this intractable disease.
    DOI:  https://doi.org/10.1172/JCI163448
  12. Mol Metab. 2022 Dec 29. pii: S2212-8778(22)00235-6. [Epub ahead of print] 101666
    Dysregulated systemic metabolism in a Down syndrome mouse model.
    Dylan C Sarver, Cheng Xu, Leandro M Velez, Susan Aja, Andrew E Jaffe, Marcus M Seldin, Roger H Reeves, G William Wong.
       OBJECTIVE: Trisomy 21 is one of the most complex genetic perturbations compatible with postnatal survival. Dosage imbalance arising from the triplication of genes on human chromosome 21 (Hsa21) affects multiple organ systems. Much of Down syndrome (DS) research, however, has focused on addressing how aneuploidy dysregulates CNS function leading to cognitive deficit. Although obesity, diabetes, and associated sequelae such as fatty liver and dyslipidemia are well documented in the DS population, only limited studies have been conducted to determine how gene dosage imbalance affects whole-body metabolism. Here, we conduct a comprehensive and systematic analysis of key metabolic parameters across different physiological states in the Ts65Dn trisomic mouse model of DS.
    METHODS: Ts65Dn mice and euploid littermates were subjected to comprehensive metabolic phenotyping under basal (chow-fed) state and the pathophysiological state of obesity induced by a high-fat diet (HFD). RNA sequencing of liver, skeletal muscle, and two major fat depots were conducted to determine the impact of aneuploidy on tissue transcriptome. Pathway enrichments, gene-centrality, and key driver estimates were performed to provide insights into tissue autonomous and non-autonomous mechanisms contributing to the dysregulation of systemic metabolism.
    RESULTS: Under the basal state, chow-fed Ts65Dn mice of both sexes had elevated locomotor activity and energy expenditure, reduced fasting serum cholesterol levels, and mild glucose intolerance. Sexually dimorphic deterioration in metabolic homeostasis became apparent when mice were challenged with a high-fat diet. While obese Ts65Dn mice of both sexes exhibited dyslipidemia, male mice also showed impaired systemic insulin sensitivity, reduced mitochondrial activity, and elevated fibrotic and inflammatory gene signatures in the liver and adipose tissue. Systems-level analysis highlighted conserved pathways and potential endocrine drivers of adipose-liver crosstalk that contribute to dysregulated glucose and lipid metabolism.
    CONCLUSIONS: A combined alteration in the expression of trisomic and disomic genes in peripheral tissues contribute to metabolic dysregulations in Ts65Dn mice. These data lay the groundwork for understanding the impact of aneuploidy on in vivo metabolism.
    Keywords:  Aneuploidy; Diabetes; Down syndrome; Insulin resistance; Obesity; Trisomy
    DOI:  https://doi.org/10.1016/j.molmet.2022.101666
  13. Front Mol Neurosci. 2022 ;15 1015220
    Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene.
    Mireia Ortega, Ilario De Toma, Álvaro Fernández-Blanco, Anna Calderón, Lucía Barahona, Ramón Trullàs, Eduard Sabidó, Mara Dierssen.
       Introduction: DYRK1A is a dual-specificity kinase that is overexpressed in Down syndrome (DS) and plays a key role in neurogenesis, neuronal differentiation and function, cognitive phenotypes, and aging. Dyrk1A has also been implicated in cerebellar abnormalities observed in association with DS, and normalization of Dyrk1A dosage rescues granular and Purkinje cell densities in a trisomic DS mouse model. However, the underlying molecular mechanisms governing these processes are unknown.
    Methods: To shed light on the effects of Dyrk1A overexpression in the cerebellum, here we investigated the cerebellar proteome in transgenic Dyrk1A overexpressing mice in basal conditions and after treatment with green tea extract containing epigallocatechin-3-gallate (EGCG), a DYRK1A inhibitor.
    Results and Discussion: Our results showed that Dyrk1A overexpression alters oxidative phosphorylation and mitochondrial function in the cerebellum of transgenic mice. These alterations are significantly rescued upon EGCG-containing green tea extract treatment, suggesting that its effects in DS could depend in part on targeting mitochondria, as shown by the partially restoration by the treatment of the increased mtDNA copy number in TG non-treated mice.
    Keywords:  DYRK1A; Down syndrome; cerebellum; mitochondria; oxidative phosphorylation system; proteomics
    DOI:  https://doi.org/10.3389/fnmol.2022.1015220
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