bims-medebr 2024-01-28 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–01–28
29 papers selected by
Regina F. Fernández, Johns Hopkins University

The metabolic overdrive hypothesis: hyperglycolysis and glutaminolysis in bipolar mania.
Astrocytes in fragile X syndrome.
Functional activation of pyruvate dehydrogenase in human brain using hyperpolarized [1-13 C]pyruvate.
Relationships of Brain Cholesterol and Cholesterol Biosynthetic Enzymes to Alzheimer's Pathology and Dementia in the CFAS Population-Derived Neuropathology Cohort.
Altered metabolism and DAM-signatures in female brains and microglia with aging.
Simultaneous fMRI and metabolic MRS of hyperpolarized [1-13 C]pyruvate during nicotine stimulus in rat.
Oligodendrocyte-axon metabolic coupling is mediated by extracellular K+ and maintains axonal health.
Metabolomic Signatures of Brainstem in Mice following Acute and Subchronic Hydrogen Sulfide Exposure.
A case of exacerbated encephalopathy with stroke-like episodes and lactic acidosis triggered by metformin in a patient with MELAS.
Amino Acid Transporters Proteins Involved in the Glutamate-Glutamine Cycle and Their Alterations in Murine Models of Alzheimer's Disease.
Bioenergetics of Axon Integrity and Its Regulation by Oligodendrocytes and Schwann Cells.
Relationship between Aspartame-Induced Cerebral Cortex Injury and Oxidative Stress, Inflammation, Mitochondrial Dysfunction, and Apoptosis in Sprague Dawley Rats.
Recent Advances in Electrochemical Detection of Cell Energy Metabolism.
Uncovering mechanisms of interorganelle lipid transport by enzymatic mass tagging.
Blood-based targeted metabolipidomics reveals altered omega fatty acid-derived lipid mediators in relapsing-remitting multiple sclerosis patients.
Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications.
Comparative Transcriptomic Analysis of Cerebellar Astrocytes across Developmental Stages and Brain Regions.
Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH2 oxidation.
Post-translational modification and mitochondrial function in Parkinson's disease.
Advances in Mass Spectrometry of Gangliosides Expressed in Brain Cancers.
Fluctuation of lysosomal protein degradation in neural stem cells of the postnatal mouse brain.
Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.
L-Lactate Treatment at 24 h and 48 h after Acute Experimental Stroke Is Neuroprotective via Activation of the L-Lactate Receptor HCA1.
Dihydroceramide desaturase governs endoplasmic reticulum and lipid droplet homeostasis to promote glial function in the nervous system.
Isolation and Enrichment of Major Primary Neuroglial Cells from Neonatal Mouse Brain.
Umbilical Cord Plasma Lysophospholipids and Triacylglycerols Associated with Birthweight Percentiles.
Aromatic L-Amino Acid Decarboxylase Deficiency: A Genetic Screening in Sicilian Patients with Neurological Disorders.
Glucose Metabolism and Cognitive Decline in Progressive Supranuclear Palsy and Corticobasal Syndrome: A Preliminary Study.
'Unpredictable chronic mild stress does not exacerbate memory impairment or altered neuronal and glial plasticity in the hippocampus of middle-aged vitamin D deficient mice'.

Mol Psychiatry. 2024 Jan 25.

The metabolic overdrive hypothesis: hyperglycolysis and glutaminolysis in bipolar mania.

Iain H Campbell, Harry Campbell.

Evidence from diverse areas of research including chronobiology, metabolomics and magnetic resonance spectroscopy indicate that energy dysregulation is a central feature of bipolar disorder pathophysiology. In this paper, we propose that mania represents a condition of heightened cerebral energy metabolism facilitated by hyperglycolysis and glutaminolysis. When oxidative glucose metabolism becomes impaired in the brain, neurons can utilize glutamate as an alternative substrate to generate energy through oxidative phosphorylation. Glycolysis in astrocytes fuels the formation of denovo glutamate, which can be used as a mitochondrial fuel source in neurons via transamination to alpha-ketoglutarate and subsequent reductive carboxylation to replenish tricarboxylic acid cycle intermediates. Upregulation of glycolysis and glutaminolysis in this manner causes the brain to enter a state of heightened metabolism and excitatory activity which we propose to underlie the subjective experience of mania. Under normal conditions, this mechanism serves an adaptive function to transiently upregulate brain metabolism in response to acute energy demand. However, when recruited in the long term to counteract impaired oxidative metabolism it may become a pathological process. In this article, we develop these ideas in detail, present supporting evidence and propose this as a novel avenue of investigation to understand the biological basis for mania.

DOI: https://doi.org/10.1038/s41380-024-02431-w
Front Cell Neurosci. 2023 ;17 1322541

Astrocytes in fragile X syndrome.

Karo Talvio, Maija L Castrén.

  Astrocytes have an important role in neuronal maturation and synapse function in the brain. The interplay between astrocytes and neurons is found to be altered in many neurodevelopmental disorders, including fragile X syndrome (FXS) that is the most common inherited cause of intellectual disability and autism spectrum disorder. Transcriptional, functional, and metabolic alterations in Fmr1 knockout mouse astrocytes, human FXS stem cell-derived astrocytes as well as in in vivo models suggest autonomous effects of astrocytes in the neurobiology of FXS. Abnormalities associated with FXS astrocytes include differentiation of central nervous system cell populations, maturation and regulation of synapses, and synaptic glutamate balance. Recently, FXS-specific changes were found more widely in astrocyte functioning, such as regulation of inflammatory pathways and maintenance of lipid homeostasis. Changes of FXS astrocytes impact the brain homeostasis and function both during development and in the adult brain and offer opportunities for novel types of approaches for intervention.

Keywords:  astrocytes; autism spectrum disorder; calcium signaling; cell differentiation; cholesterol; fragile X syndrome; glutamate; induced pluripotent stem cells

DOI:  https://doi.org/10.3389/fncel.2023.1322541
Magn Reson Med. 2024 Jan 24.

Functional activation of pyruvate dehydrogenase in human brain using hyperpolarized [1-13 C]pyruvate.

Maheen Zaidi, Junjie Ma, Binu P Thomas, Salvador Peña, Crystal E Harrison, Jun Chen, Sung-Han Lin, Kelley A Derner, Jeannie D Baxter, Jeff Liticker, Craig R Malloy, Brenda Bartnik-Olson, Jae Mo Park.

   PURPOSE: Pyruvate, produced from either glucose, glycogen, or lactate, is the dominant precursor of cerebral oxidative metabolism. Pyruvate dehydrogenase (PDH) flux is a direct measure of cerebral mitochondrial function and metabolism. Detection of [13 C]bicarbonate in the brain from hyperpolarized [1-13 C]pyruvate using carbon-13 (13 C) MRI provides a unique opportunity for assessing PDH flux in vivo. This study is to assess changes in cerebral PDH flux in response to visual stimuli using in vivo 13 C MRS with hyperpolarized [1-13 C]pyruvate.
METHODS: From seven sedentary adults in good general health, time-resolved [13 C]bicarbonate production was measured in the brain using 90° flip angles with minimal perturbation of its precursors, [1-13 C]pyruvate and [1-13 C]lactate, to test the hypothesis that the appearance of [13 C]bicarbonate signals in the brain reflects the metabolic changes associated with neuronal activation. With a separate group of healthy participants (n = 3), the likelihood of the bolus-injected [1-13 C]pyruvate being converted to [1-13 C]lactate prior to decarboxylation was investigated by measuring [13 C]bicarbonate production with and without [1-13 C]lactate saturation.
RESULTS: In the course of visual stimulation, the measured [13 C]bicarbonate signal normalized to the total 13 C signal in the visual cortex increased by 17.1% ± 15.9% (p = 0.017), whereas no significant change was detected in [1-13 C]lactate. Proton BOLD fMRI confirmed the regional activation in the visual cortex with the stimuli. Lactate saturation decreased bicarbonate-to-pyruvate ratio by 44.4% ± 9.3% (p < 0.01).
CONCLUSION: We demonstrated the utility of 13 C MRS with hyperpolarized [1-13 C]pyruvate for assessing the activation of cerebral PDH flux via the detection of [13 C]bicarbonate production.

Keywords:  bicarbonate; brain activation; dissolution dynamic nuclear polarization; fMRS; hyperpolarized pyruvate; pyruvate dehydrogenase

DOI:  https://doi.org/10.1002/mrm.30015
Neurosci Res. 2024 Jan 24. pii: S0168-0102(24)00007-5. [Epub ahead of print]

Relationships of Brain Cholesterol and Cholesterol Biosynthetic Enzymes to Alzheimer's Pathology and Dementia in the CFAS Population-Derived Neuropathology Cohort.

Cognitive Function and Ageing Study

  Altered cholesterol metabolism is implicated in brain ageing and Alzheimer's disease. We examined whether key genes regulating cholesterol metabolism and levels of brain cholesterol are altered in dementia and Alzheimer's disease neuropathological change (ADNC). Temporal cortex (n=99) was obtained from the Cognitive Function and Ageing Study. Expression of the cholesterol biosynthesis rate-limiting enzyme HMG-CoA reductase (HMGCR) and its regulator, SREBP2, were detected using immunohistochemistry. Expression of HMGCR, SREBP2, CYP46A1 and ABCA1 were quantified by qPCR in samples enriched for astrocyte and neuronal RNA following laser-capture microdissection. Total cortical cholesterol was measured using the Amplex Red assay. HMGCR and SREBP2 proteins were predominantly expressed in pyramidal neurones, and in glia. Neuronal HMGCR did not vary with ADNC, oxidative stress, neuroinflammation or dementia status. Expression of HMGCR neuronal mRNA decreased with ADNC (p=0.022) and increased with neuronal DNA damage (p=0.049), whilst SREBP2 increased with ADNC (p=0.005). High or moderate tertiles for cholesterol levels were associated with increased dementia risk (OR 1.44, 1.58). APOE ε4 allele was not associated with cortical cholesterol levels. ADNC is associated with gene expression changes that may impair cholesterol biosynthesis in neurones but not astrocytes, whilst levels of cortical cholesterol show a weak relationship to dementia status.

Keywords:  Alzheimer’s disease; Cognitive Function and Ageing Study; HMG-CoA reductase; cholesterol; dementia; sterol regulatory element-binding proteins

DOI:  https://doi.org/10.1016/j.neures.2024.01.003
Brain Res. 2024 Jan 18. pii: S0006-8993(24)00026-X. [Epub ahead of print] 148772

Altered metabolism and DAM-signatures in female brains and microglia with aging.

Nicholas R W Cleland, Garrett J Potter, Courtney Buck, Daphne Quang, Dean Oldham, Mikaela Neal, Anthony Saviola, Christy S Niemeyer, Evgenia Dobrinskikh, Kimberley D Bruce.

  Despite Alzheimer's disease (AD) disproportionately affecting women, the mechanisms remain elusive. In AD, microglia undergo 'metabolic reprogramming', which contributes to microglial dysfunction and AD pathology. However, how sex and age contribute to metabolic reprogramming in microglia is understudied. Here, we use metabolic imaging, transcriptomics, and metabolic assays to probe age-and sex-associated changes in brain and microglial metabolism. Glycolytic and oxidative metabolism in the whole brain was determined using Fluorescence Lifetime Imaging Microscopy (FLIM). Young female brains appeared less glycolytic than male brains, but with aging, the female brain became 'male-like.' Transcriptomic analysis revealed increased expression of disease-associated microglia (DAM) genes (e.g., ApoE, Trem2, LPL), and genes involved in glycolysis and oxidative metabolism in microglia from aged females compared to males. To determine whether estrogen can alter the expression of these genes, BV-2 microglia-like cell lines, which abundantly express DAM genes, were supplemented with 17β-estradiol (E2). E2 supplementation resulted in reduced expression of DAM genes, reduced lipid and cholesterol transport, and substrate-dependent changes in glycolysis and oxidative metabolism. Consistent with the notion that E2 may suppress DAM-associated factors, LPL activity was elevated in the brains of aged female mice. Similarly, DAM gene and protein expression was higher in monocyte-derived microglia-like (MDMi) cells derived from middle-aged females compared to age-matched males and was responsive to E2 supplementation. FLIM analysis of MDMi from young and middle-aged females revealed reduced oxidative metabolism and FAD + with age. Overall, our findings show that altered metabolism defines age-associated changes in female microglia and suggest that estrogen may inhibit the expression and activity of DAM-associated factors, which may contribute to increased AD risk, especially in post-menopausal women.

Keywords:  Aging; Alzheimer’s disease; Lipids; Lipoprotein lipase; Metabolism; Microglia; Sex-differences

DOI:  https://doi.org/10.1016/j.brainres.2024.148772
NMR Biomed. 2024 Jan 25.

Simultaneous fMRI and metabolic MRS of hyperpolarized [1-13 C]pyruvate during nicotine stimulus in rat.

Viivi-Elina A Hyppönen, Jessica Rosa, Mikko I Kettunen.

  Functional MRI (fMRI) and MRS (fMRS) can be used to noninvasively map cerebral activation and metabolism. Recently, hyperpolarized 13 C spectroscopy and metabolic imaging have provided an alternative approach to assess metabolism. In this study, we combined 1 H fMRI and hyperpolarized [1-13 C]pyruvate MRS to compare cerebral blood oxygenation level-dependent (BOLD) response and real-time cerebral metabolism, as assessed with lactate and bicarbonate labelling, during nicotine stimulation. Simultaneous 1 H fMRI (multislice gradient echo echo-planar imaging) and 13 C spectroscopic (single slice pulse-acquire) data were collected in urethane-anaesthetized female Sprague-Dawley rats (n = 12) at 9.4 T. Animals received an intravenous (i.v.) injection of either nicotine (stimulus; 88 μg/kg, n = 7, or 300 μg/kg, n = 5) or 0.9% saline (matching volume), followed by hyperpolarized [1-13 C]pyruvate injection 60 s later. Three hours later, a second injection was administered: the animals that had previously received saline were injected with nicotine and vice versa, both followed by another hyperpolarized [1-13 C]pyruvate i.v. injection 60 s later. The low-dose (88 μg/kg) nicotine injection led to a 12% ± 4% (n = 7, t-test, p ~ 0.0006 (t-value -5.8, degrees of freedom 6), Wilcoxon p ~ 0.0078 (test statistic 0)) increase in BOLD signal. At the same time, an increase in 13 C-bicarbonate signal was seen in four out of six animals. Bicarbonate-to-total carbon ratios were 0.010 ± 0.004 and 0.018 ± 0.010 (n = 6, t-test, p ~ 0.03 (t-value -2.3, degrees of freedom 5), Wilcoxon p ~ 0.08 (test statistic 3)) for saline and nicotine experiments, respectively. No increase in the lactate signal was seen; lactate-to-total carbon was 0.16 ± 0.02 after both injections. The high (300 μg/kg) nicotine dose (n = 5) caused highly variable BOLD and metabolic responses, possibly due to the apparent respiratory distress. Simultaneous detection of 1 H fMRI and hyperpolarized 13 C-MRS is feasible. A comparison of metabolic response between control and stimulated states showed differences in bicarbonate signal, implying that the hyperpolarization technique could offer complimentary information on brain activation.

Keywords:  BOLD; brain metabolism; dDNP MRS; fMRI; hyperpolarized [1-13C]pyruvate; nicotine

DOI:  https://doi.org/10.1002/nbm.5108
Nat Neurosci. 2024 Jan 24.

Oligodendrocyte-axon metabolic coupling is mediated by extracellular K+ and maintains axonal health.

Zoe J Looser, Zainab Faik, Luca Ravotto, Henri S Zanker, Ramona B Jung, Hauke B Werner, Torben Ruhwedel, Wiebke Möbius, Dwight E Bergles, L Felipe Barros, Klaus-Armin Nave, Bruno Weber, Aiman S Saab.

The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs). To determine how OLs detect axonal spiking and how rapid axon-OL metabolic coupling is regulated in the white matter, we studied activity-dependent calcium (Ca2+) and metabolite fluxes in the mouse optic nerve. We show that fast axonal spiking triggers Ca2+ signaling and glycolysis in OLs. OLs detect axonal activity through increases in extracellular potassium (K+) concentrations and activation of Kir4.1 channels, thereby regulating metabolite supply to axons. Both pharmacological inhibition and OL-specific inactivation of Kir4.1 reduce the activity-induced axonal lactate surge. Mice lacking oligodendroglial Kir4.1 exhibit lower resting lactate levels and altered glucose metabolism in axons. These early deficits in axonal energy metabolism are associated with late-onset axonopathy. Our findings reveal that OLs detect fast axonal spiking through K+ signaling, making acute metabolic coupling possible and adjusting the axon-OL metabolic unit to promote axonal health.

DOI: https://doi.org/10.1038/s41593-023-01558-3
Metabolites. 2024 Jan 14. pii: 53. [Epub ahead of print]14(1):

Metabolomic Signatures of Brainstem in Mice following Acute and Subchronic Hydrogen Sulfide Exposure.

Dong-Suk Kim, Cristina M Santana Maldonado, Cecilia Giulivi, Wilson Kiiza Rumbeiha.

  Hydrogen sulfide (H2S) is an environmental toxicant of significant health concern. The brain is a major target in acute H2S poisoning. This study was conducted to test the hypothesis that acute and subchronic ambient H2S exposures alter the brain metabolome. Male 7-8-week-old C57BL/6J mice were exposed by whole-body inhalation to 1000 ppm H2S for 45 min and euthanized at 5 min or 72 h for acute exposure. For subchronic study, mice were exposed to 5 ppm H2S 2 h/day, 5 days/week for 5 weeks. Control mice were exposed to room air. The brainstem was removed for metabolomic analysis. Enrichment analysis showed that the metabolomic profiles in acute and subchronic H2S exposures matched with those of cerebral spinal fluid from patients with seizures or Alzheimer's disease. Acute H2S exposure decreased excitatory neurotransmitters, aspartate, and glutamate, while the inhibitory neurotransmitter, serotonin, was increased. Branched-chain amino acids and glucose were increased by acute H2S exposure. Subchronic H2S exposure within OSHA guidelines surprisingly decreased serotonin concentration. In subchronic H2S exposure, glucose was decreased, while polyunsaturated fatty acids, inosine, and hypoxanthine were increased. Collectively, these results provide important mechanistic clues for acute and subchronic ambient H2S poisoning and show that H2S alters brainstem metabolome.

Keywords:  biomarkers; brain; brainstem; branched-chain amino acids; hydrogen sulfide; metabolism; metabolomics; neurotransmitters; polyunsaturated fatty acids

DOI:  https://doi.org/10.3390/metabo14010053
Neurol Sci. 2024 Jan 24.

A case of exacerbated encephalopathy with stroke-like episodes and lactic acidosis triggered by metformin in a patient with MELAS.

Hui Jin Shin, Ji-Hoon Na, Young-Mock Lee.

  Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited multisystemic disorder caused by mutations in mitochondrial DNA that result in cellular energy deficiency. MELAS affects the most metabolically active organs, including the brain, skeletal muscles, cochlea, retina, heart, kidneys, and pancreas. As a result, about 85% of carriers of m.3243A > G, the most common mutation in MELAS, develop diabetes by the age of 70. Although metformin is the most widely prescribed drug for diabetes, its usefulness in mitochondrial dysfunction remains controversial. Here, we present the case of a 32-year-old Korean patient diagnosed with MELAS who presented with exacerbated stroke-like episodes and lactic acidosis triggered by metformin.

Keywords:  DNA, Mitochondrial; MELAS syndrome; Metformin; Point mutation; Seizures

DOI:  https://doi.org/10.1007/s10072-024-07343-9
Mol Neurobiol. 2024 Jan 26.

Amino Acid Transporters Proteins Involved in the Glutamate-Glutamine Cycle and Their Alterations in Murine Models of Alzheimer's Disease.

Diana Laura Vázquez-Durán, Arturo Ortega, Angelina Rodríguez.

  The brain's ability to integrate external stimuli and generate responses is highly complex. While these mechanisms are not completely understood, current evidence suggests that alterations in cellular metabolism and microenvironment are involved in some dysfunctions as complex as Alzheimer's disease. This pathology courses with defects in the establishment of chemical synapses, which is dependent on the production and supply of neurotransmitters like glutamate and its recycling through the glutamate-glutamine cycle. Alterations in the expression and function of the amino acid transporters proteins involved in this cycle have recently been reported in different stages of Alzheimer's disease. Most of these data come from patients in advanced stages of the disease or post-mortem, due to the ethical and technical limitations of human studies. Therefore, genetically modified mouse models have been an excellent tool to analyze metabolic and even behavioral parameters that are very similar to those that develop in Alzheimer's disease, even at presymptomatic stages. Hence, this paper analyzes the role of glutamate metabolism and its intercellular trafficking in excitatory synapses from different approaches using transgenic mouse models; such an analysis will contribute to our present understanding of AD.

Keywords:  Alzheimer’s disease; Amino acid transporter; Glutamate-Glutamine Cycle

DOI:  https://doi.org/10.1007/s12035-024-03966-3
Mol Neurobiol. 2024 Jan 22.

Bioenergetics of Axon Integrity and Its Regulation by Oligodendrocytes and Schwann Cells.

Sandeep K Mishra, Sandip Prasad Tiwari.

  Axons are long slender portions of neurons that transmit electrical impulses to maintain proper physiological functioning. Axons in the central nervous system (CNS) and peripheral nervous system (PNS) do not exist in isolation but are found to form a complex association with their surrounding glial cells, oligodendrocytes and Schwann cells. These cells not only myelinate them for faster nerve impulse conduction but are also known to provide metabolic support. Due to their incredible length, continuous growth, and distance from the cell body (where major energy synthesis takes place), axons are in high energetic demand. The stability and integrity of axons have long been associated with axonal energy levels. The current mini-review is thus focused on how axons accomplish their high energetic requirement in a cell-autonomous manner and how the surrounding glial cells help them in maintaining their integrity by fulfilling their energy demands (non-cell autonomous trophic support). The concept that adjacent glial cells (oligodendrocytes and Schwann cells) provide trophic support to axons and assist them in maintaining their integrity comes from the conditional knockout research and the studies in which the metabolic pathways controlling metabolism in these glial cells are modulated and its effect on axonal integrity is evaluated. In the later part of the mini-review, the current knowledge of axon-glial metabolic coupling during various neurodegenerative conditions was discussed, along with the potential lacunae in our current understanding of axon-glial metabolic coupling.

Keywords:  Axon; Bioenergetics; Metabolic coupling; Oligodendrocytes; Schwann cells

DOI:  https://doi.org/10.1007/s12035-024-03950-x
Antioxidants (Basel). 2023 Dec 19. pii: 2. [Epub ahead of print]13(1):

Relationship between Aspartame-Induced Cerebral Cortex Injury and Oxidative Stress, Inflammation, Mitochondrial Dysfunction, and Apoptosis in Sprague Dawley Rats.

Jureeporn U-Pathi, Yen-Chia Yeh, Chia-Wen Chen, Eddy E Owaga, Rong-Hong Hsieh.

  There are emerging concerns about the potential cerebral cortex injury from aspartame due to the accumulation of the various neurotoxic metabolic components in the central nervous system after long-term dietary exposure. The aim of this study was to evaluate the effect of oral aspartame consumption on cerebral cortex injury in the rat brain, and further evaluate the various underlying molecular mechanisms, with a special focus on oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis pathways. Sprague Dawley rats (nineteen, female) were randomly sub-divided into three groups: (i) normal diet with vehicle: control group (five rats), (ii) low dose of aspartame group (LA): seven rats received 30 mg/kg body weight (bw) daily doses of aspartame, (iii) high dose of aspartame group (HA): seven rats received 60 mg/kg bw daily doses of aspartame. After 8 weeks, the LA and HA groups showed lower expression levels of brain-derived neurotrophic factor (BDNF), antioxidant enzyme activity (SOD2, CAT), antioxidant marker (Nrf2), inflammatory response (IκB), mitochondrial biogenesis (Sirt1, PGC1α, Nrf1, TFAM), mitochondrial DNA (mtDNA) copy number, and apoptosis-related proteins (Bax, Caspase-3) expressions. Aspartame administration also elevated oxidative stress levels (Malondialdehyde, MDA), 8-hydroxy-2-deoxy guanosine (8-OHdG), PGE2 and COX-2 expressions, pro-inflammatory cytokines (TNFα, IL6, IL1β), antioxidant marker expression (Keap1), inflammatory responses (iNOS, NFκB), and glial fibrillary acidic protein (GFAP) levels in the cerebral cortex of the rats, thereby contributing to the reduced survival of pyramidal cells and astrocyte glial cells of the cerebral cortex. Therefore, these findings imply that aspartame-induced neurotoxicity in rats' cerebral cortex could be regulated through four mechanisms: inflammation, enhanced oxidant stress, decreased mitochondrial biogenesis, and apoptosis pathways.

Keywords:  apoptosis; aspartame; inflammation; mitochondrial biogenesis; oxidative stress

DOI:  https://doi.org/10.3390/antiox13010002
Biosensors (Basel). 2024 Jan 15. pii: 46. [Epub ahead of print]14(1):

Recent Advances in Electrochemical Detection of Cell Energy Metabolism.

Kyeong-Mo Koo, Chang-Dae Kim, Tae-Hyung Kim.

  Cell energy metabolism is a complex and multifaceted process by which some of the most important nutrients, particularly glucose and other sugars, are transformed into energy. This complexity is a result of dynamic interactions between multiple components, including ions, metabolic intermediates, and products that arise from biochemical reactions, such as glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), the two main metabolic pathways that provide adenosine triphosphate (ATP), the main source of chemical energy driving various physiological activities. Impaired cell energy metabolism and perturbations or dysfunctions in associated metabolites are frequently implicated in numerous diseases, such as diabetes, cancer, and neurodegenerative and cardiovascular disorders. As a result, altered metabolites hold value as potential disease biomarkers. Electrochemical biosensors are attractive devices for the early diagnosis of many diseases and disorders based on biomarkers due to their advantages of efficiency, simplicity, low cost, high sensitivity, and high selectivity in the detection of anomalies in cellular energy metabolism, including key metabolites involved in glycolysis and mitochondrial processes, such as glucose, lactate, nicotinamide adenine dinucleotide (NADH), reactive oxygen species (ROS), glutamate, and ATP, both in vivo and in vitro. This paper offers a detailed examination of electrochemical biosensors for the detection of glycolytic and mitochondrial metabolites, along with their many applications in cell chips and wearable sensors.

Keywords:  cell chip; electrochemical biosensor; glycolytic metabolites; mitochondrial metabolites; wearable sensor

DOI:  https://doi.org/10.3390/bios14010046
FEBS Lett. 2024 Jan 24.

Uncovering mechanisms of interorganelle lipid transport by enzymatic mass tagging.

Arun T John Peter, Benoit Kornmann.

  Lipid trafficking is critical for the biogenesis and expansion of organelle membranes. Lipid transport proteins (LTPs) have been proposed to facilitate lipid transport at contact sites between organelles. Despite the fundamental importance of LTPs in cell physiology, our knowledge on the mechanisms of interorganelle lipid distribution remains poor due to the scarcity of assays to monitor lipid flux in vivo. In this review, we highlight the recent development of a versatile method named METALIC (Mass tagging-Enabled Tracking of Lipids in Cells), which uses a combination of enzymatic mass tagging and mass spectrometry to track lipid flux between organelles inside living cells. We discuss the methodology, its distinct advantages, limitations as well as its potential to unearth the pipelines of lipid transport and LTP function in vivo.

Keywords:  CFAse; METALIC; cyclopropane fatty acid; lipid trafficking; lipid transport assay; lipid transport protein; lipidomics; mass tagging; membrane contact sites; phospholipid

DOI:  https://doi.org/10.1002/1873-3468.14810
bioRxiv. 2024 Jan 06. pii: 2024.01.04.574253. [Epub ahead of print]

Blood-based targeted metabolipidomics reveals altered omega fatty acid-derived lipid mediators in relapsing-remitting multiple sclerosis patients.

Insha Zahoor, Jeffrey Waters, Nasar Ata, Indrani Datta, Theresa L Pedersen, Mirela Cerghet, Laila Poisson, Silva Markovic-Plese, Ramandeep Rattan, Ameer Y Taha, John W Newman, Shailendra Giri.

Unresolved and uncontrolled inflammation is considered a hallmark of pathogenesis in chronic inflammatory diseases like multiple sclerosis (MS), suggesting a defective resolution process. Inflammatory resolution is an active process partially mediated by endogenous metabolites of dietary polyunsaturated fatty acids (PUFA), collectively termed specialized pro-resolving lipid mediators (SPMs). Altered levels of resolution mediators have been reported in several inflammatory diseases and may partly explain impaired inflammatory resolution. Performing LC-MS/MS-based targeted lipid mediator profiling, we observed distinct changes in fatty acid metabolites in serum from 30 relapsing-remitting MS (RRMS) patients relative to 30 matched healthy subjects (HS). Robust linear regression revealed 12 altered lipid mediators after adjusting for confounders (p <0.05). Of these, 15d-PGJ2, PGE3, and LTB5 were increased in MS while PGF2a, 8,9-DiHETrE, 5,6-DiHETrE, 20-HETE, 15-HETE, 12-HETE, 12-HEPE, 14-HDoHE, and DHEA were decreased in MS compared to HS. In addition, 12,13-DiHOME and 12,13-DiHODE were positively correlated with expanded disability status scale values (EDSS). Using Partial Least Squares, we identified several lipid mediators with high VIP scores (VIP > 1: 32% - 52%) of which POEA, PGE3, DHEA, LTB5, and 12-HETE were top predictors for distinguishing between RRMS and HS (AUC =0.75) based on the XGBoost Classifier algorithm. Collectively, these findings suggest an imbalance between inflammation and resolution. Altogether, lipid mediators appear to have potential as diagnostic and prognostic biomarkers for RRMS.

DOI: https://doi.org/10.1101/2024.01.04.574253
Front Psychiatry. 2023 ;14 1301272

Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications.

Peter Balicza, Andras Gezsi, Mariann Fedor, Judit C Sagi, Aniko Gal, Noemi Agnes Varga, Maria Judit Molnar.

  We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carrier male. This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category.

Keywords:  MECP2 mutation; RNA sequencing; Rett syndrome; anxiety; cariprazine; learning disability; mitochondrial dysfunction; negative symptoms

DOI:  https://doi.org/10.3389/fpsyt.2023.1301272
Int J Mol Sci. 2024 Jan 13. pii: 1021. [Epub ahead of print]25(2):

Comparative Transcriptomic Analysis of Cerebellar Astrocytes across Developmental Stages and Brain Regions.

Wookbong Kwon, Dong-Joo Choi, Kwanha Yu, Michael R Williamson, Sanjana Murali, Yeunjung Ko, Junsung Woo, Benjamin Deneen.

  Astrocytes are the most abundant glial cell type in the central nervous system, and they play a crucial role in normal brain function. While gliogenesis and glial differentiation occur during perinatal cerebellar development, the processes that occur during early postnatal development remain obscure. In this study, we conducted transcriptomic profiling of postnatal cerebellar astrocytes at postnatal days 1, 7, 14, and 28 (P1, P7, P14, and P28), identifying temporal-specific gene signatures at each specific time point. Comparing these profiles with region-specific astrocyte differentially expressed genes (DEGs) published for the cortex, hippocampus, and olfactory bulb revealed cerebellar-specific gene signature across these developmental timepoints. Moreover, we conducted a comparative analysis of cerebellar astrocyte gene signatures with gene lists from pediatric brain tumors of cerebellar origin, including ependymoma and medulloblastoma. Notably, genes downregulated at P14, such as Kif11 and HMGB2, exhibited significant enrichment across all pediatric brain tumor groups, suggesting the importance of astrocytic gene repression during cerebellar development to these tumor subtypes. Collectively, our studies describe gene expression patterns during cerebellar astrocyte development, with potential implications for pediatric tumors originating in the cerebellum.

Keywords:  astrocyte; cerebellum; pediatric brain tumors; postnatal development; transcriptome

DOI:  https://doi.org/10.3390/ijms25021021
Geroscience. 2024 Jan 25.

Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH2 oxidation.

Roman Abrosimov, Marius W Baeken, Samuel Hauf, Ilka Wittig, Parvana Hajieva, Carmen E Perrone, Bernd Moosmann.

  Inhibition of mitochondrial complex I (NADH dehydrogenase) is the primary mechanism of the antidiabetic drug metformin and various unrelated natural toxins. Complex I inhibition can also be induced by antidiabetic PPAR agonists, and it is elicited by methionine restriction, a nutritional intervention causing resistance to diabetes and obesity. Still, a comprehensible explanation to why complex I inhibition exerts antidiabetic properties and engenders metabolic inefficiency is missing. To evaluate this issue, we have systematically reanalyzed published transcriptomic datasets from MPP-treated neurons, metformin-treated hepatocytes, and methionine-restricted rats. We found that pathways leading to NADPH formation were widely induced, together with anabolic fatty acid biosynthesis, the latter appearing highly paradoxical in a state of mitochondrial impairment. However, concomitant induction of catabolic fatty acid oxidation indicated that complex I inhibition created a "futile" cycle of fatty acid synthesis and degradation, which was anatomically distributed between adipose tissue and liver in vivo. Cofactor balance analysis unveiled that such cycling would indeed be energetically futile (-3 ATP per acetyl-CoA), though it would not be redox-futile, as it would convert NADPH into respirable FADH2 without any net production of NADH. We conclude that inhibition of NADH dehydrogenase leads to a metabolic shift from glycolysis and the citric acid cycle (both generating NADH) towards the pentose phosphate pathway, whose product NADPH is translated 1:1 into FADH2 by fatty acid cycling. The diabetes-resistant phenotype following hepatic and intestinal complex I inhibition is attributed to FGF21- and GDF15-dependent fat hunger signaling, which remodels adipose tissue into a glucose-metabolizing organ.

Keywords:  Diabetes; FGF21; Metformin; Methionine restriction; NADH dehydrogenase; Peroxisome proliferator-activated receptor

DOI:  https://doi.org/10.1007/s11357-023-01059-y
Front Mol Neurosci. 2023 ;16 1329554

Post-translational modification and mitochondrial function in Parkinson's disease.

Shishi Luo, Danling Wang, Zhuohua Zhang.

  Parkinson's disease (PD) is the second most common neurodegenerative disease with currently no cure. Most PD cases are sporadic, and about 5-10% of PD cases present a monogenic inheritance pattern. Mutations in more than 20 genes are associated with genetic forms of PD. Mitochondrial dysfunction is considered a prominent player in PD pathogenesis. Post-translational modifications (PTMs) allow rapid switching of protein functions and therefore impact various cellular functions including those related to mitochondria. Among the PD-associated genes, Parkin, PINK1, and LRRK2 encode enzymes that directly involved in catalyzing PTM modifications of target proteins, while others like α-synuclein, FBXO7, HTRA2, VPS35, CHCHD2, and DJ-1, undergo substantial PTM modification, subsequently altering mitochondrial functions. Here, we summarize recent findings on major PTMs associated with PD-related proteins, as enzymes or substrates, that are shown to regulate important mitochondrial functions and discuss their involvement in PD pathogenesis. We will further highlight the significance of PTM-regulated mitochondrial functions in understanding PD etiology. Furthermore, we emphasize the potential for developing important biomarkers for PD through extensive research into PTMs.

Keywords:  Parkinson’s disease; SUMOylation; acetylation; mitochondrial function; phosphorylation; post-translational modification (PTM); s-nitrosylation; ubiquitination

DOI:  https://doi.org/10.3389/fnmol.2023.1329554
Int J Mol Sci. 2024 Jan 22. pii: 1335. [Epub ahead of print]25(2):

Advances in Mass Spectrometry of Gangliosides Expressed in Brain Cancers.

Maria Roxana Biricioiu, Mirela Sarbu, Raluca Ica, Željka Vukelić, Svjetlana Kalanj-Bognar, Alina D Zamfir.

  Gangliosides are highly abundant in the human brain where they are involved in major biological events. In brain cancers, alterations of ganglioside pattern occur, some of which being correlated with neoplastic transformation, while others with tumor proliferation. Of all techniques, mass spectrometry (MS) has proven to be one of the most effective in gangliosidomics, due to its ability to characterize heterogeneous mixtures and discover species with biomarker value. This review highlights the most significant achievements of MS in the analysis of gangliosides in human brain cancers. The first part presents the latest state of MS development in the discovery of ganglioside markers in primary brain tumors, with a particular emphasis on the ion mobility separation (IMS) MS and its contribution to the elucidation of the gangliosidome associated with aggressive tumors. The second part is focused on MS of gangliosides in brain metastases, highlighting the ability of matrix-assisted laser desorption/ionization (MALDI)-MS, microfluidics-MS and tandem MS to decipher and structurally characterize species involved in the metastatic process. In the end, several conclusions and perspectives are presented, among which the need for development of reliable software and a user-friendly structural database as a search platform in brain tumor diagnostics.

Keywords:  biomarker discovery; brain cancers; gangliosides; mass spectrometry; screening; structural analysis

DOI:  https://doi.org/10.3390/ijms25021335
Development. 2024 Jan 24. pii: dev.202231. [Epub ahead of print]

Fluctuation of lysosomal protein degradation in neural stem cells of the postnatal mouse brain.

He Zhang, Karan Ishii, Tatsuya Shibata, Shunsuke Ishii, Marika Hirao, Zhou Lu, Risa Takamura, Satsuki Kitano, Hitoshi Miyachi, Ryoichiro Kageyama, Eisuke Itakura, Taeko Kobayashi.

  Lysosomes are intracellular organelles responsible for degrading diverse macromolecules delivered from several pathways, including the endo-lysosomal and autophagic pathways. Recent reports have suggested that lysosomes are essential for regulating neural stem cells in developing, adult, and aged brains. However, the activity of these lysosomes has yet to be monitored in these brain tissues. Here, we report the development of a new probe to measure lysosomal protein degradation in brain tissue by immunostaining. Our results indicate that lysosomal protein degradation fluctuates in neural stem cells of the hippocampal dentate gyrus, depending on age and brain disorders. Neural stem cells increase their lysosomal activity during hippocampal development in the dentate gyrus, but aging and aging-related disease reduce lysosomal activity. In addition, physical exercise increases lysosomal activity in neural stem cells and astrocytes in the dentate gyrus. We therefore propose that three different stages of lysosomal activity exist: the state of increase during development, the stable state during adulthood, and the state of reduction due to damage caused by either age or disease.

Keywords:  Adult brain; Dentate gyrus; Lysosomes; Neural stem cells; Protein degradation

DOI:  https://doi.org/10.1242/dev.202231
Neurotherapeutics. 2024 Jan 19. pii: S1878-7479(24)00002-3. [Epub ahead of print]21(1): e00316

Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.

Daniel G Calame, Lisa T Emrick.

  Mitochondria are critical for brain development and homeostasis. Therefore, pathogenic variation in the mitochondrial or nuclear genome which disrupts mitochondrial function frequently results in developmental disorders and neurodegeneration at the organismal level. Large-scale application of genome-wide technologies to individuals with mitochondrial diseases has dramatically accelerated identification of mitochondrial disease-gene associations in humans. Multi-omic and high-throughput studies involving transcriptomics, proteomics, metabolomics, and saturation genome editing are providing deeper insights into the functional consequence of mitochondrial genomic variation. Integration of deep phenotypic and genomic data through allelic series continues to uncover novel mitochondrial functions and permit mitochondrial gene function dissection on an unprecedented scale. Finally, mitochondrial disease-gene associations illuminate disease mechanisms and thereby direct therapeutic strategies involving small molecules and RNA-DNA therapeutics. This review summarizes progress in functional genomics and small molecule therapeutics in mitochondrial neurodevelopmental disorders.

Keywords:  Functional genomics; Mitochondrial disease; Neurodevelopmental disorders; Small molecules; Therapeutics

DOI:  https://doi.org/10.1016/j.neurot.2024.e00316
Int J Mol Sci. 2024 Jan 19. pii: 1232. [Epub ahead of print]25(2):

L-Lactate Treatment at 24 h and 48 h after Acute Experimental Stroke Is Neuroprotective via Activation of the L-Lactate Receptor HCA1.

Samuel J Geiseler, Alena Hadzic, Marvin Lambertus, Karl Martin Forbord, Ghazal Sajedi, Arthur Liesz, Cecilie Morland.

  Stroke is the main cause for acquired disabilities. Pharmaceutical or mechanical removal of the thrombus is the cornerstone of stroke treatment but can only be administered to a subset of patients and within a narrow time window. Novel treatment options are therefore required. Here we induced stroke by permanent occlusion of the distal medial cerebral artery of wild-type mice and knockout mice for the lactate receptor hydroxycarboxylic acid receptor 1 (HCA1). At 24 h and 48 h after stroke induction, we injected L-lactate intraperitoneal. The resulting atrophy was measured in Nissl-stained brain sections, and capillary density and neurogenesis were measured after immunolabeling and confocal imaging. In wild-type mice, L-lactate treatment resulted in an HCA1-dependent reduction in the lesion volume accompanied by enhanced angiogenesis. In HCA1 knockout mice, on the other hand, there was no increase in angiogenesis and no reduction in lesion volume in response to L-lactate treatment. Nevertheless, the lesion volumes in HCA1 knockout mice-regardless of L-lactate treatment-were smaller than in control mice, indicating a multifactorial role of HCA1 in stroke. Our findings suggest that L-lactate administered 24 h and 48 h after stroke is protective in stroke. This represents a time window where no effective treatment options are currently available.

Keywords:  GPR81; HCA1; HCAR1; L-lactate; angiogenesis; dMCAO; exercise; stroke; vascularization

DOI:  https://doi.org/10.3390/ijms25021232
bioRxiv. 2024 Jan 02. pii: 2024.01.01.573836. [Epub ahead of print]

Dihydroceramide desaturase governs endoplasmic reticulum and lipid droplet homeostasis to promote glial function in the nervous system.

Yuqing Zhu, Kevin Cho, Haluk Lacin, Yi Zhu, Jose DiPaola, Beth A Wilson, Gary J Patti, James B Skeath.

Dihydroceramide desaturases convert dihydroceramides to ceramides in the last step of the de novo ceramide pathway. Reduction of DEGS1 dihydroceramide desaturase function in humans leads to the rare neurodegenerative disorder hypomyelinating leukodystrophy-18, but the exact mechanism that underlies the disease remains unclear. Through a forward genetic screen, we discovered that infertile crescent (ifc) , the sole Drosophila dihydroceramide desaturase, governs central nervous system development and morphology. Expressed and genetically active most prominently in glia rather than neurons, ifc primarily controls nervous system development through a cell autonomous function in glia. Within the nervous system, loss of ifc results in ceramide depletion, dihydroceramide accumulation, and increased saturation of major membrane phospholipids. At the cellular level, loss of ifc leads to severe glial defects, particularly in cortex glia, including expansion of the endoplasmic reticulum, cell swelling, failure to enwrap neurons, and lipid droplet depletion. Our research supports a model in which inappropriate retention of dihydroceramide in the endoplasmic reticulum (ER) of glial cells drives ER expansion and cell swelling, disrupting glial function and leading to subsequent nervous system dysfunction. Given the conserved nature of the de novo ceramide biosynthesis pathway, our findings in the fly system suggest that dihydroceramide-triggered expansion of the ER in the membrane-rich glial cells may be the proximal cause of hypomyelinating leukodystrophy-18 in humans.

DOI: https://doi.org/10.1101/2024.01.01.573836
Bio Protoc. 2024 Jan 20. 14(2): e4921

Isolation and Enrichment of Major Primary Neuroglial Cells from Neonatal Mouse Brain.

Santosh Kumar Samal, Madhav Sharma, Jayasri Das Sarma.

  The central nervous system (CNS) relies on the complex interaction of neuroglial cells to carry out vital physiological functions. To comprehensively understand the structural and functional interplay between these neuroglial cells, it is essential to establish an appropriate in vitro system that can be utilized for thorough investigation. Traditional protocols for establishing primary neuronal and mixed glial cultures from prenatal mice or neural stem cells require sacrificing pregnant mice and have the drawback of yielding only specific types of cells. Our current protocol overcomes these drawbacks by utilizing the brain from day-0 pups to isolate CNS resident neuroglial cells including astrocytes, microglia, oligodendrocytes [oligodendrocyte precursor cells (OPCs) and differentiated oligodendrocytes], and meningeal fibroblasts, as well as hippocampal neurons, avoiding sacrificing pregnant mice, which makes this procedure efficient and cost effective. Furthermore, through this protocol, we aim to provide step-by-step instructions for isolating and establishing different primary neuroglial cells and their characterization using cell-specific markers. This study presents an opportunity to isolate, culture, and establish all major CNS resident cells individually. These cells can be utilized in various cell-based and biochemical assays to comprehensively investigate the cell-specific roles and behaviors of brain resident cells in a reductionist approach. Key features • Efficient isolation of major neuroglial cells like meningeal fibroblasts, neurons, astrocytes, oligodendrocytes, and microglia from a single day-0 neonatal mouse pup's brain. • Circumvents the sacrifice of pregnant female mice. • Acts as a bridging experimental method between secondary cell lines and in vivo systems. • Isolated cells can be used for performing various cell-based and biochemical assays.

Keywords:  Astrocytes; Cell culture; In vitro; Meningeal fibroblasts; Microglia; Neurons; Oligodendrocytes; Primary-cells

DOI:  https://doi.org/10.21769/BioProtoc.4921
Nutrients. 2024 Jan 17. pii: 274. [Epub ahead of print]16(2):

Umbilical Cord Plasma Lysophospholipids and Triacylglycerols Associated with Birthweight Percentiles.

Gerard Wong, Kothandaraman Narasimhan, Wei Fun Cheong, Sharon Ng, Izzuddin M Aris, See Ling Loy, Anne K Bendt, Kok Hian Tan, Fabian K P Yap, Lynette P Shek, Yap Seng Chong, Peter D Gluckman, Keith M Godfrey, Yung Seng Lee, Markus R Wenk, Neerja Karnani, Shiao-Yng Chan.

  Dysregulated transplacental lipid transfer and fetal-placental lipid metabolism affect birthweight, as does maternal hyperglycemia. As the mechanisms are unclear, we aimed to identify the lipids in umbilical cord plasma that were most associated with birthweight. Seventy-five Chinese women with singleton pregnancies recruited into the GUSTO mother-offspring cohort were selected from across the glycemic range based on a mid-gestation 75 g oral glucose tolerance test, excluding pre-existing diabetes. Cord plasma samples collected at term delivery were analyzed using targeted liquid-chromatography tandem mass-spectrometry to determine the concentrations of 404 lipid species across 17 lipid classes. The birthweights were standardized for sex and gestational age by local references, and regression analyses were adjusted for the maternal age, BMI, parity, mode of delivery, insulin treatment, and fasting/2 h glucose, with a false discovery-corrected p < 0.05 considered significant. Ten lysophosphatidylcholines (LPCs) and two lysophosphatidylethanolamines were positively associated with the birthweight percentiles, while twenty-four triacylglycerols were negatively associated with the birthweight percentiles. The topmost associated lipid was LPC 20:2 [21.28 (95%CI 12.70, 29.87) percentile increase in the standardized birthweight with each SD-unit increase in log10-transformed concentration]. Within these same regression models, maternal glycemia did not significantly associate with the birthweight percentiles. Specific fetal circulating lysophospholipids and triacylglycerols associate with birthweight independently of maternal glycemia, but a causal relationship remains to be established.

Keywords:  GUSTO; fetal growth; lipidomics; lysophosphatidylcholine; triacylglycerol; umbilical cord blood

DOI:  https://doi.org/10.3390/nu16020274
Genes (Basel). 2024 Jan 21. pii: 134. [Epub ahead of print]15(1):

Aromatic L-Amino Acid Decarboxylase Deficiency: A Genetic Screening in Sicilian Patients with Neurological Disorders.

Sandro Santa Paola, Francesco Domenico Di Blasi, Eugenia Borgione, Mariangela Lo Giudice, Marika Giuliano, Rosa Pettinato, Vincenzo Di Stefano, Filippo Brighina, Antonino Lupica, Carmela Scuderi.

  Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare autosomal recessive neurometabolic disorder caused by AADC deficiency, an enzyme encoded by the DDC gene. Since the enzyme is involved in the biosynthesis of serotonin and dopamine, its deficiency determines the lack of these neurotransmitters, but also of norepinephrine and epinephrine. Onset is early and the key signs are hypotonia, movement disorders (oculogyric crises, dystonia and hypokinesia), developmental delay and autonomic dysfunction. Taiwan is the site of a potential founder variant (IVS6+4A>T) with a predicted incidence of 1/32,000 births, while only 261 patients with this deficit have been described worldwide. Actually, the number of affected persons could be greater, given that the spectrum of clinical manifestations is broad and still little known. In our study we selected 350 unrelated patients presenting with different neurological disorders including heterogeneous neuromuscular disorders, cognitive deficit, behavioral disorders and autism spectrum disorder, for which the underlying etiology had not yet been identified. Molecular investigation of the DDC gene was carried out with the aim of identifying affected patients and/or carriers. Our study shows a high frequency of carriers (2.57%) in Sicilian subjects with neurological deficits, with a higher concentration in northern and eastern Sicily. Assuming these data as representative of the general Sicilian population, the risk may be comparable to some rare diseases included in the newborn screening programs such as spinal muscular atrophy, cystic fibrosis and phenylketonuria.

Keywords:  AADCD; Sicily; aromatic L-amino acid decarboxylase deficiency; cognitive deficit; neuromuscular defect

DOI:  https://doi.org/10.3390/genes15010134
J Clin Med. 2024 Jan 14. pii: 465. [Epub ahead of print]13(2):

Glucose Metabolism and Cognitive Decline in Progressive Supranuclear Palsy and Corticobasal Syndrome: A Preliminary Study.

Natalia Madetko-Alster, Dagmara Otto-Ślusarczyk, Marta Struga, Michał Kutyłowski, Agnieszka Drzewińska, Karolina Duszyńska-Wąs, Bartosz Migda, Piotr Alster.

  Multiple studies have analyzed the possible correlations between diabetes and Alzheimer's disease. Less is known about the context of cognitive deterioration among patients with atypical Parkinsonian syndromes and glucose metabolism impairment. The aim of this study was to evaluate the association between the impaired glucose metabolism and cognitive decline among patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The study included 22 patients with PSP and CBS with disease durations varying from 3 to 6 years. The levels of glycated hemoglobin (HbA1C), fasting blood glucose, fasting C-peptide and the presence of microalbuminuria were evaluated, and oral glucose tolerance tests (OGTT) were performed. Based on the OGTT results, the glycemic variability, mean glycemia, glycemia standard deviation (SD) and coefficient of variation (%CV) were calculated. All patients underwent a three-Tesla brain magnetic resonance (MRI) examination and neuropsychological cognitive assessment with the use of standardized scales: Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). A statistical analysis revealed that poor control of glycemia with high glycemic variability and increased atrophy of the medial temporal lobe among patients with PSP and CBS correlated with worse cognitive performance independent of age or sex, even among patients who did not fulfill the criteria for diabetes. The study results indicate the importance of glucose metabolism control and optimal treatment in the context of cognition maintenance among patients with PSP and CBS. Due to the relatively small number of analyzed patients, the issue requires further assessment. To the best of our knowledge, this is the first study discussing the role of glycemic variability in atypical Parkinsonian syndromes.

Keywords:  atypical Parkinsonian syndrome; cognitive impairment; corticobasal syndrome; glycemic variability; impaired glucose metabolism; progressive supranuclear palsy

DOI:  https://doi.org/10.3390/jcm13020465
Eur J Neurosci. 2024 Jan 25.

'Unpredictable chronic mild stress does not exacerbate memory impairment or altered neuronal and glial plasticity in the hippocampus of middle-aged vitamin D deficient mice'.

Kelli Somelar-Duracz, Monika Jürgenson, Janeli Viil, Alexander Zharkovsky, Külli Jaako.

  Vitamin D deficiency is a worldwide health concern, especially in the elderly population. Much remains unknown about the relationship between vitamin D deficiency (VDD), stress-induced cognitive dysfunctions and depressive-like behaviour. In this study, 4-month-old male C57Bl/6J mice were fed with control or vitamin D free diet for 6 months, followed by unpredictable chronic stress (UCMS) for 8 weeks. VDD induced cognitive impairment and reduced grooming behaviour, but did not induce depressive-like behaviour. While UCMS in vitamin D sufficient mice induced expected depressive-like phenotype and impairments in the contextual fear memory, chronic stress did not manifest as an additional risk factor for memory impairments and depressive-like behaviour in VDD mice. In fact, UCMS restored self-care behaviour in VDD mice. At the histopathological level, VDD mice exhibited cell loss in the granule cell layer, reduced survival of newly generated cells, accompanied with an increased number of apoptotic cells and alterations in glial morphology in the hippocampus; however, these effects were not exacerbated by UCMS. Interestingly, UCMS reversed VDD induced loss of microglial cells. Moreover, tyrosine hydroxylase levels decreased in the striatum of VDD mice, but not in stressed VDD mice. These findings indicate that long-term VDD in adulthood impairs cognition but does not augment behavioural response to UCMS in middle-aged mice. While VDD caused cell loss and altered glial response in the DG of the hippocampus, these effects were not exacerbated by UCMS and could contribute to mechanisms regulating altered stress response.

Keywords:  chronic stress; fear memory; grooming behaviour; neurogenesis; neuroinflammation

DOI:  https://doi.org/10.1111/ejn.16256