bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2024‒05‒05
fifteen papers selected by
Regina F. Fernández, Johns Hopkins University



  1. EMBO Rep. 2024 Apr 29.
      The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, but its role in disease pathogenesis is unknown. Here, we show alterations in glucose metabolic pathways and ATP levels in the brains of asymptomatic C9-BAC mice. We find that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also show that one of the arginine-rich DPRs (PR) could directly contribute to glucose metabolism and metabolic stress by inhibiting glucose uptake in neurons. Our findings provide a potential mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and suggest a feedforward loop model with potential opportunities for therapeutic intervention.
    Keywords:  ALS; C9orf72; FTD; Glucose Hypometabolism; RAN Translation
    DOI:  https://doi.org/10.1038/s44319-024-00140-7
  2. Clin Neurol Neurosurg. 2024 Apr 30. pii: S0303-8467(24)00194-X. [Epub ahead of print]241 108307
      Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease mostly associated with severe lactic acidosis, rapid progression of neurological symptoms and death during childhood. We present a 33-year-old male with PDC deficiency caused by a Val262Leu mutation in PDHA1gene. He demonstrated generalized dystonia affecting trunk and upper extremities and paraparesis as the most significant features, with onset of symptoms at age 8. Brain MRI showed bilaterally increased signal within the globus pallidus, typical of Leigh syndrome. A periodic lactate increase in serum and cerebrospinal fluid was detected. We describe a case of pyruvate dehydrogenase deficiency being diagnosed only 25 years after the onset of symptoms and highlight PDHC deficiency as a possible cause of treatable dystonia in childhood, which may respond well to thiamine and levodopa treatment.
    Keywords:  Deep brain stimulation; Dystonia; Pyruvate dehydrogenase-E1α deficiency
    DOI:  https://doi.org/10.1016/j.clineuro.2024.108307
  3. J Inherit Metab Dis. 2024 May 01.
      Humans derive fatty acids (FA) from exogenous dietary sources and/or endogenous synthesis from acetyl-CoA, although some FA are solely derived from exogenous sources ("essential FA"). Once inside cells, FA may undergo a wide variety of different modifications, which include their activation to their corresponding CoA ester, the introduction of double bonds, the 2- and ω-hydroxylation and chain elongation, thereby generating a cellular FA pool which can be used for the synthesis of more complex lipids. The biological properties of complex lipids are very much determined by their molecular composition in terms of the FA incorporated into these lipid species. This immediately explains the existence of a range of genetic diseases in man, often with severe clinical consequences caused by variants in one of the many genes coding for enzymes responsible for these FA modifications. It is the purpose of this review to describe the current state of knowledge about FA homeostasis and the genetic diseases involved. This includes the disorders of FA activation, desaturation, 2- and ω-hydroxylation, and chain elongation, but also the disorders of FA breakdown, including disorders of peroxisomal and mitochondrial α- and β-oxidation.
    Keywords:  (phospho)lipid metabolism; 2‐hydroxylation; fatty acid elongation; mitochondrial disorders; peroxisomal disorders; sphingolipid metabolism; ω‐hydroxylation
    DOI:  https://doi.org/10.1002/jimd.12734
  4. Alzheimers Dement (Amst). 2024 Apr-Jun;16(2):16(2): e12587
      Gamma-hydroxy-butyric acid (GABA) and glutamate are neurotransmitters with essential importance for cognitive processing. Here, we investigate relationships between GABA, glutamate, and brain ß-amyloid (Aß) burden before clinical manifestation of Alzheimer's disease (AD). Thirty cognitively healthy adults (age 69.9 ± 6 years) received high-resolution atlas-based 1H-magnetic resonance spectroscopic imaging (MRSI) at ultra-high magnetic field strength of 7 Tesla for gray matter-specific assessment of GABA and glutamate. We assessed Aß burden with positron emission tomography and risk factors for AD. Higher gray matter GABA and glutamate related to higher Aß-burden (ß = 0.60, p < 0.05; ß = 0.64, p < 0.02), with positive effect modification by apolipoprotein-E-epsilon-4-allele (APOE4) (p = 0.01-0.03). GABA and glutamate negatively related to longitudinal change in verbal episodic memory performance (ß = -0.48; p = 0.02; ß = -0.50; p = 0.01). In vivo measures of GABA and glutamate reflect early AD pathology at old age, in an APOE4-dependent manner. GABA and glutamate may represent promising biomarkers and potential targets for early therapeutic intervention and prevention.Highlights: Gray matter-specific metabolic imaging with high-resolution atlas-based MRSI at 7 Tesla.Higher GABA and glutamate relate to ß-amyloid burden, in an APOE4-dependent manner.Gray matter GABA and glutamate identify older adults with high risk of future AD.GABA and glutamate might reflect altered synaptic and neuronal activity at early AD.
    Keywords:  7 Tesla; APOE4; Alzheimer; GABA; aging; beta‐amyloid; biomarker; cognitive impairment; dementia; glutamate; magnetic resonance spectroscopic imaging; magnetic resonance spectroscopy; memory; positron emission tomography; prevention; synaptic dysfunction; synaptic metabolism
    DOI:  https://doi.org/10.1002/dad2.12587
  5. Ann Med Surg (Lond). 2024 May;86(5): 3086-3089
      Introduction: The authors identify two patterns of inheritance in a Syrian child from consanguineous parents. The membrane-bound O-acyltranferase domain-containing7 (MBOAT7) gene encodes Lysophosphatidylinositol acyltranferase (LPIAT1), which is responsible for the neurodevelopment of the brain cortex. Patients with MBOAT7 variants exhibit pathogenic nervous manifestations such as global developmental delays affecting speech and motor function, intellectual disability (ID), poor coordination, and seizures, with or without MRI abnormalities. MT_TS1, the mitochondrial tRNASer(UCN) gene, is a hotspot for pathogenic mutations causing variable mitochondrial phenotypes, including hearing impairment (HI), ataxia and cognitive impairment.Clinical presentation: The authors present a case of a 4-year-old child with motor and speech delay, truncal hypotonia, visual tic, poor coordination, autistic features and generalized seizures at 7 months of age. After normal results from lab tests and MRI imaging, along with the family's history of neurological disorders, genetic analysis was necessary to diagnose and assess the possibility of genetic counselling. Next-generation sequencing (NGS) showed two variable variants in the MBOAT7 and MT-TS1 genes. The first mutation is a homozygous variant of uncertain significance in the MBOAT7 gene, associated with the autosomal recessive Mental retardation type 57. The second variant is a heteroplasmic pathogenic variant in the MT-TS1 gene, indicative of mitochondrial disorders.
    Conclusion: The presence of the MBOAT7 and MT-TS1 gene variants in the same child is noteworthy. The authors must keep genetic mutations of MBOAT7 and MT-TS1 gene in mind as a differential diagnosis for intellectual disability, seizures and autistic features in children, especially in consanguineous families.
    Keywords:  MBOAT7; MT-TS1; delayed psychomotor development
    DOI:  https://doi.org/10.1097/MS9.0000000000001941
  6. J Neurochem. 2024 May 01.
      Positron emission tomography (PET) imaging studies in laboratory animals are almost always performed under isoflurane anesthesia to ensure that the subject stays still during the image acquisition. Isoflurane is effective, safe, and easy to use, and it is generally assumed to not have an impact on the imaging results. Motivated by marked differences observed in the brain uptake and metabolism of the PET tracer 3-[18F]fluoro-4-aminopyridine [(18F]3F4AP) between human and nonhuman primate studies, this study investigates the possible effect of isoflurane on this process. Mice received [18F]3F4AP injection while awake or under anesthesia and the tracer brain uptake and metabolism was compared between groups. A separate group of mice received the known cytochrome P450 2E1 inhibitor disulfiram prior to tracer administration. Isoflurane was found to largely abolish tracer metabolism in mice (74.8 ± 1.6 vs. 17.7 ± 1.7% plasma parent fraction, % PF) resulting in a 4.0-fold higher brain uptake in anesthetized mice at 35 min post-radiotracer administration. Similar to anesthetized mice, animals that received disulfiram showed reduced metabolism (50.0 ± 6.9% PF) and a 2.2-fold higher brain signal than control mice. The higher brain uptake and lower metabolism of [18F]3F4AP observed in anesthetized mice compared to awake mice are attributed to isoflurane's interference in the CYP2E1-mediated breakdown of the tracer, which was confirmed by reproducing the effect upon treatment with the known CYP2E1 inhibitor disulfiram. These findings underscore the critical need to examine the effect of isoflurane in PET imaging studies before translating tracers to humans that will be scanned without anesthesia.
    Keywords:  PET imaging; [18F]3F4AP; anesthesia; metabolism; radiometabolites; radiotracer
    DOI:  https://doi.org/10.1111/jnc.16118
  7. Nature. 2024 May 01.
      Choline is an essential nutrient that the human body needs in vast quantities for cell membrane synthesis, epigenetic modification and neurotransmission. The brain has a particularly high demand for choline, but how it enters the brain remains unknown1-3. The major facilitator superfamily transporter FLVCR1 (also known as MFSD7B or SLC49A1) was recently determined to be a choline transporter but is not highly expressed at the blood-brain barrier, whereas the related protein FLVCR2 (also known as MFSD7C or SLC49A2) is expressed in endothelial cells at the blood-brain barrier4-7. Previous studies have shown that mutations in human Flvcr2 cause cerebral vascular abnormalities, hydrocephalus and embryonic lethality, but the physiological role of FLVCR2 is unknown4,5. Here we demonstrate both in vivo and in vitro that FLVCR2 is a BBB choline transporter and is responsible for the majority of choline uptake into the brain. We also determine the structures of choline-bound FLVCR2 in both inward-facing and outward-facing states using cryo-electron microscopy. These results reveal how the brain obtains choline and provide molecular-level insights into how FLVCR2 binds choline in an aromatic cage and mediates its uptake. Our work could provide a novel framework for the targeted delivery of therapeutic agents into the brain.
    DOI:  https://doi.org/10.1038/s41586-024-07326-y
  8. Biomed Pharmacother. 2024 Apr 30. pii: S0753-3322(24)00572-9. [Epub ahead of print]175 116688
      Metabolic syndrome (MetS) is characterized by insulin resistance, hyperglycemia, excessive fat accumulation and dyslipidemia, and is known to be accompanied by neuropathological symptoms such as memory loss, anxiety, and depression. As the number of MetS patients is rapidly increasing globally, studies on the mechanisms of metabolic imbalance-related neuropathology are emerging as an important issue. Ca2+/calmodulin-dependent kinase II (CaMKII) is the main Ca2+ sensor and contributes to diverse intracellular signaling in peripheral organs and the central nervous system (CNS). CaMKII exerts diverse functions in cells, related to mechanisms such as RNA splicing, reactive oxygen species (ROS) generation, cytoskeleton, and protein-protein interactions. In the CNS, CaMKII regulates vascular function, neuronal circuits, neurotransmission, synaptic plasticity, amyloid beta toxicity, lipid metabolism, and mitochondrial function. Here, we review recent evidence for the role of CaMKII in neuropathologic issues associated with metabolic disorders.
    Keywords:  CaMKII; Cognitive impairment; Metabolic syndromes (MetS); Neuropathology; Vascular dysfunction
    DOI:  https://doi.org/10.1016/j.biopha.2024.116688
  9. Cell Mol Biol (Noisy-le-grand). 2024 Apr 28. 70(4): 100-106
      Nervonic acid (NA) is a primary long-chain fatty acid and has been confirmed to have neuroprotective effects in neurologic diseases. Oxidative stress and neuronal damage are the main causes of Parkinson's disease (PD). This study mainly explored whether NA is involved in regulating oxidative stress and apoptosis in MPTP-induced mouse model and MPP-induced cell model. Through behavior tests, we proved that MPTP-induced motor dysfunction in mice was recovered by NA treatment. NA can reduce MPTP-induced neuronal damage, manifested by elevated levels of TH and dopamine, as well as decreased levels of α-syn. In the in vitro model, we observed from CCK8 assay and flow cytometry that the induction of MPP markedly suppressed cell activity and enhanced cell apoptosis, but these functions were all reversed by NA. Furthermore, NA administration reversed the increase in ROS production and MDA levels induced by MPTP or MPP, as well as the decrease in SOD levels, suggesting the antioxidant properties of NA in PD. Meanwhile, we confirmed that NA can regulate oxidative stress and neuronal damage by activating the MEK/ERK pathway. Overall, we concluded that NA could alleviate MPTP-induced PD via MEK/ERK pathway.
    DOI:  https://doi.org/10.14715/cmb/2024.70.4.16
  10. Nat Commun. 2024 Apr 29. 15(1): 3631
      Idiopathic Parkinson's disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.
    DOI:  https://doi.org/10.1038/s41467-024-47867-4
  11. FEBS Lett. 2024 May 02.
      Lipid metabolism hinges on a balance between lipogenesis and fatty acid oxidation (FAO). Disruptions in this balance can induce endoplasmic reticulum (ER) stress triggering the unfolded protein response (UPR) and contribute to metabolic diseases. The UPR protein, Luman or CREB3, has recently been implicated in metabolic regulation-CREB3 knockout mice exhibit resistance to diet-induced obesity and altered insulin sensitivity. Here, we show that CREB3 activated PPARGC1A transcription from a 1 kb promoter region. An increase in CREB3 expression correlated inversely with endogenous PPARGC1A mRNA levels and genes involved in FAO. As PGC-1α encoded by PPARGC1A is a master regulator of mitochondrial biogenesis and energy homeostasis, these findings demonstrate that CREB3 is a transcriptional regulator of PGC-1α, underlining the potential role of CREB3 in energy metabolism.
    Keywords:  CREB3; PGC‐1α; endoplasmic reticulum stress; fatty acid oxidation; metabolism; transcriptional regulation
    DOI:  https://doi.org/10.1002/1873-3468.14897
  12. J Neuroinflammation. 2024 Apr 29. 21(1): 113
      Obesity increases the morbidity and mortality of traumatic brain injury (TBI). Detailed analyses of transcriptomic changes in the brain and adipose tissue were performed to elucidate the interactive effects between high-fat diet-induced obesity (DIO) and TBI. Adult male mice were fed a high-fat diet (HFD) for 12 weeks prior to experimental TBI and continuing after injury. High-throughput transcriptomic analysis using Nanostring panels of the total visceral adipose tissue (VAT) and cellular components in the brain, followed by unsupervised clustering, principal component analysis, and IPA pathway analysis were used to determine shifts in gene expression patterns and molecular pathway activity. Cellular populations in the cortex and hippocampus, as well as in VAT, during the chronic phase after combined TBI-HFD showed amplification of central and peripheral microglia/macrophage responses, including superadditive changes in selected gene expression signatures and pathways. Furthermore, combined TBI and HFD caused additive dysfunction in Y-Maze, Novel Object Recognition (NOR), and Morris water maze (MWM) cognitive function tests. These novel data suggest that HFD-induced obesity and TBI can independently prime and support the development of altered states in brain microglia and VAT, including the disease-associated microglia/macrophage (DAM) phenotype observed in neurodegenerative disorders. The interaction between HFD and TBI promotes a shift toward chronic reactive microglia/macrophage transcriptomic signatures and associated pro-inflammatory disease-altered states that may, in part, underlie the exacerbation of cognitive deficits. Thus, targeting of HFD-induced reactive cellular phenotypes, including in peripheral adipose tissue immune cell populations, may serve to reduce microglial maladaptive states after TBI, attenuating post-traumatic neurodegeneration and neurological dysfunction.
    Keywords:  Cognition; Disease-associated microglia; Microglia; Neuroinflammation; Obesity; Traumatic brain injury; Visceral adipose tissue
    DOI:  https://doi.org/10.1186/s12974-024-03107-6
  13. Cell Rep. 2024 Apr 26. pii: S2211-1247(24)00476-5. [Epub ahead of print] 114148
      Coenzyme Q (CoQ) deficiency syndrome is conventionally treated with limited efficacy using exogenous CoQ10. Poor outcomes result from low absorption and bioavailability of CoQ10 and the clinical heterogenicity of the disease. Here, we demonstrate that supplementation with 4-hydroxybenzoic acid (4HB), the precursor of the benzoquinone ring in the CoQ biosynthetic pathway, completely rescues multisystemic disease and perinatal lethality in a mouse model of CoQ deficiency. 4HB stimulates endogenous CoQ biosynthesis in tissues of Coq2 mutant mice, normalizing mitochondrial function and rescuing cardiac insufficiency, edema, and neurodevelopmental delay. In contrast, exogenous CoQ10 supplementation falls short in fully restoring the phenotype. The treatment is translatable to human use, as proven by in vitro studies in skin fibroblasts from patients with pathogenic variants in COQ2. The therapeutic approach extends to other disorders characterized by deficiencies in the production of 4HB and early steps of CoQ biosynthesis and instances of secondary CoQ deficiency.
    Keywords:  4-hydroxybenzoic acid; CP: Metabolism; CoQ biosynthesis; cardiac insufficiency; coenzyme Q deficiency; metabolic disorders; mitochondrial diseases; neurodevelopmental disorders; perinatal lethality; pharmacological therapy; translational medicine
    DOI:  https://doi.org/10.1016/j.celrep.2024.114148
  14. J Transl Med. 2024 May 03. 22(1): 419
      BACKGROUND: Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se.METHODS: VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis.
    RESULTS: VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis.
    CONCLUSIONS: VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.
    Keywords:  Glioblastoma; Mitochondria; Mitochondrial transcription factor A; Peroxisome proliferator-activated receptor gamma coactivator 1-α/PGC1α; Reactive oxygen species; Vascular endothelial growth factor receptor 2
    DOI:  https://doi.org/10.1186/s12967-024-05155-1
  15. J Neurotrauma. 2024 May 02.
      Moderate traumatic brain injury (mTBI) involves a series of complex pathophysiological processes in not only the area in direct contact with mechanical violence but also other brain regions far from the injury site, which may be important factors influencing subsequent neurological dysfunction or death. The medulla oblongata (MO) is a key area for the maintenance of basic respiratory and circulatory functions, whereas the pathophysiological processes after mTBI have rarely drawn the attention of researchers. In this study, we established a closed-head cortical contusion injury model, identified 6 different time points that covered the acute, subacute and chronic phases, and then used nontargeted metabolomics to identify and analyse the changes in differential metabolites (DMs) and metabolic pathways in the MO region. Our results showed that the metabolic profile of the MO region underwent specific changes over time: harmaline, riboflavin and dephospho-coenzyme A were identified as the key DMs and play important roles in reducing inflammation, enhancing antioxidation and maintaining homeostasis. Choline and glycerophospholipid metabolism were identified as the key pathways related to the changes in MO metabolism at different phases. In addition, we confirmed increases in the levels of inflammatory factors and the activation of astrocytes and microglia by Western blot and immunofluorescence staining, and these findings were consistent with the nontargeted metabolomics results. These findings suggest that neuroinflammation plays a central role in MO neuropathology after mTBI and provide new insights into the complex pathophysiologic mechanisms involved after mTBI.
    Keywords:  ANIMAL STUDIES; INFLAMMATION; TRAUMATIC BRAIN INJURY
    DOI:  https://doi.org/10.1089/neu.2023.0536