bims-medebr 2025-01-19 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–01–19
twenty-six papers selected by
Regina F. Fernández, Johns Hopkins University

Specific activity of mouse liver desaturases and elongases: Time course effects using n-3 and n-6 PUFA substrates and inhibitory responses of delta-6 desaturase.
Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease.
Age-Trajectories of Higher-Order Diffusion Properties of Major Brain Metabolites in Cerebral and Cerebellar Gray Matter Using In Vivo Diffusion-Weighted MR Spectroscopy at 3T.
Abnormal Redox Balance at Membrane Contact Sites Causes Axonopathy in Gdap1-related Charcot-marie-tooth Disease.
ATAD1 Regulates Neuronal Development and Synapse Formation Through Tuning Mitochondrial Function.
Complex I deficiency remains the most frequent cause of Leigh syndrome spectrum.
Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.
Past, present and future of research on brain energy metabolism in bipolar disorder.
Glycogen synthase GYS1 overactivation contributes to glycogen insolubility and malto-oligoglucan-associated neurodegenerative disease.
Long-Term Creatine Supplementation Improves Cognitive and Hippocampal Structural Plasticity Impairments in a D-Gal-Induced Aging Model via Increasing CK-BB Activity in the Brain.
Ketogenic Diet as a Nutritional Metabolic Intervention for Obsessive-Compulsive Disorder: A Narrative Review.
Identification of a metabolic brain network characterizing essential tremor.
Exploring In Vivo Human Brain Metabolism at 10.5 T: Initial Insights from MR Spectroscopic Imaging.
Noncanonical PI(4,5)P2 coordinates lysosome positioning through cholesterol trafficking.
The role of lipid metabolism in cognitive impairment.
Mitochondrial HMG-CoA synthase deficiency.
Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in H3K27M-mutant gliomas.
Molecular Mechanisms Linking Omega-3 Fatty Acids and the Gut-Brain Axis.
Phosphorylation of N-glycans in the brain: The case for a non-canonical pathway?
The role of mitochondrial remodeling in neurodegenerative diseases.
Interaction and regulation of the mitochondrial proteome - in health and disease.
Progressive Loss of Cerebral Structures in ALG11-Related Congenital Disorder Glycosylation.
Metabolomic in severe traumatic brain injury: exploring primary, secondary injuries, diagnosis, and severity.
Quantitative Lipidomics of Biological Samples Using Supercritical Fluid Chromatography Mass Spectrometry.
SIRT2 and ALDH1A1 as critical enzymes for astrocytic GABA production in Alzheimer's disease.
Constitutive loss of kynurenine-3-monooxygenase changes circulating kynurenine metabolites without affecting systemic energy metabolism.

Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jan 10. pii: S1388-1981(25)00002-2. [Epub ahead of print]1870(2): 159594

Specific activity of mouse liver desaturases and elongases: Time course effects using n-3 and n-6 PUFA substrates and inhibitory responses of delta-6 desaturase.

Rodrigo Valenzuela, Adam H Metherel, Giulia Cisbani, Mackenzie E Smith, Raphaël Chouinard-Watkins, Brinley J Klievik, Camila Farias, Luis A Videla, Richard P Bazinet.

  The synthesis of n-3 and n-6 polyunsaturated acids (PUFAs) is associated with physiological functions in mammals, being catalyzed by Δ-5D and Δ-6D desaturases and elongases Elovl-2 and Elovl-5. In this context, we aimed to study the chief kinetic features of PUFA liver anabolism, looking upon (i) the time-dependency for the specific activity of Δ-6D, Δ-5D, Elovl2, Elovl2/5 and Elovl5, using n-3 and n-6 precursors between 0 and 240 min ex vivo in mouse liver.; and (ii) the specific activity-substrate (α-linolenic acid; ALA) concentration responses of Δ-6D in the absence and presence of linoleic acid (LA), arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), an enzyme regarded as the rate-limiting step in PUFA anabolism. Mouse liver was obtained from eight-week-old Balb/c mice fed a chow diet (expressed as % of total calories: 18 % fat, 24 % protein, and 58 % carbohydrate, with a caloric value of 3.1 kcal/g) for eight weeks, and used for preparation of the microsomal fraction. Enzymatic activities assayed under the addition of specific PUFA precursors or LA, ARA, EPA and DHA, identifying the respective PUFA products as fatty acid methyl esters by gas chromatographic analysis. Data described corroborate that (i) PUFA metabolism mainly occurs in the liver, with the participating enzymes preferring n-3 than n-6 substrates; and show that (ii) the rate-limiting step of PUFA metabolism relies on the second reaction of Δ-6D (24:5n-3 transformed to 24:6n-3); and (iii) LA, ARA, EPA and DHA act as non-competitive inhibitors with respect to ALA in the reaction catalyzed by Δ-6D. These results are relevant for future studies concerning the metabolic and nutritional implications of changes in desaturation and elongation of PUFAs.

Keywords:  Inhibitory responses; Liver; PUFA desaturation activity; PUFA elongation activity; Polyunsaturated fatty acids (PUFAs); Time course relations

DOI:  https://doi.org/10.1016/j.bbalip.2025.159594
Neurobiol Dis. 2025 Jan 08. pii: S0969-9961(25)00014-2. [Epub ahead of print]205 106798

Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease.

Wenxuan Wang, Sarah J Myers, Nikita Ollen-Bittle, Shawn N Whitehead.

  Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for two-thirds of all dementia cases, and age is the strongest risk factor. In addition to the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a class of membrane lipids of the glycosphingolipid family and are enriched in the central nervous system (CNS). Ganglioside dysregulation has been implicated in various neurodegenerative diseases, including AD, but the spatial distribution of ganglioside dysregulation with respect to amyloid-beta (Aβ) deposition is not well understood. To address this gap, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was employed to investigate the age-dependent expression profiles of the A-series ganglioside species GD1a, GM1, GM2, and GM3 in the APP/PS1 transgenic mouse model of AD in which age-dependent amyloid-beta (Aβ) plaques develop. This study utilized a dual-resolution approach in combination with whole-brain imaging for comprehensive detection of ganglioside expression across neuroanatomical regions via high-resolution imaging of the cerebral cortex and hippocampus to investigate plaque-associated ganglioside alterations. The results revealed age-dependent changes in the complex gangliosides GM1 and GD1a across white and gray matter regions in both wildtype and APP/PS1 mice. Significantly greater levels of simple gangliosides GM2 and GM3 were observed in the cortex and dentate gyrus of the hippocampus in transgenic mice at 12 and 18 m than in age-matched controls. The accumulation of GM3 colocalized with Aβ plaques in aged APP/PS1 mice and correlated with Hexa gene expression, suggesting that ganglioside degradation is a mechanism for the accumulation of GM3. This work is the first to demonstrate that age-related ganglioside dysregulation is spatiotemporally associated with Aβ plaques using sophisticated MSI and reveals novel mechanistic insights into lipid regulation in AD.

Keywords:  Aging; Alzheimer's disease; Amyloid; Ganglioside; HexA; Lipid dysregulation; Mass spectrometry imaging

DOI:  https://doi.org/10.1016/j.nbd.2025.106798
Aging Cell. 2025 Jan 16. e14477

Age-Trajectories of Higher-Order Diffusion Properties of Major Brain Metabolites in Cerebral and Cerebellar Gray Matter Using In Vivo Diffusion-Weighted MR Spectroscopy at 3T.

Kadir Şimşek, Cécile Gallea, Guglielmo Genovese, Stephane Lehéricy, Francesca Branzoli, Marco Palombo.

  Healthy brain aging involves changes in both brain structure and function, including alterations in cellular composition and microstructure across brain regions. Unlike diffusion-weighted MRI (dMRI), diffusion-weighted MR spectroscopy (dMRS) can assess cell-type specific microstructural changes, providing indirect information on both cell composition and microstructure through the quantification and interpretation of metabolites' diffusion properties. This work investigates age-related changes in the higher-order diffusion properties of total N-Acetyl-aspartate (neuronal biomarker), total choline (glial biomarker), and total creatine (both neuronal and glial biomarker) beyond the classical apparent diffusion coefficient in cerebral and cerebellar gray matter of healthy human brain. Twenty-five subjects were recruited and scanned using a diffusion-weighted semi-LASER sequence in two brain regions-of-interest (ROI) at 3T: posterior-cingulate (PCC) and cerebellar cortices. Metabolites' diffusion was characterized by quantifying metrics from both Gaussian and non-Gaussian signal representations and biophysical models. All studied metabolites exhibited lower apparent diffusivities and higher apparent kurtosis values in the cerebellum compared to the PCC, likely stemming from the higher microstructural complexity of cellular composition in the cerebellum. Multivariate regression analysis (accounting for ROI tissue composition as a covariate) showed slight decrease (or no change) of all metabolites' diffusivities and slight increase of all metabolites' kurtosis with age, none of which statistically significant (p > 0.05). The proposed age-trajectories provide benchmarks for identifying anomalies in the diffusion properties of major brain metabolites which could be related to pathological mechanisms altering both the brain microstructure and cellular composition.

Keywords:  aging; cerebellum; cerebral cortex; diffusion modeling; gray matter; magnetic resonance spectroscopy; metabolite

DOI:  https://doi.org/10.1111/acel.14477
Res Sq. 2024 Dec 31. pii: rs.3.rs-5682984. [Epub ahead of print]

Abnormal Redox Balance at Membrane Contact Sites Causes Axonopathy in Gdap1-related Charcot-marie-tooth Disease.

Francesc Palau, Lara Cantarero, Mónica Roldán, María Rodríguez-Sanz, Angela Mathison, Yaiza Díaz-Osorio, Jordi Pijuan, Marcos Frías, Raul Urrutia, Janet Hoenicka.

Pathogenic variants of GDAP1 cause Charcot-Marie-Tooth disease (CMT), an inherited neuropathy characterized by axonal degeneration. GDAP1, an atypical glutathione S-transferase, localizes to the outer mitochondrial membrane (OMM), regulating this organelle's dynamics, transport, and membrane contact sites (MCSs). It has been proposed that GDAP1 functions as a cellular redox sensor. However, its precise contribution to redox homeostasis remains poorly understood, as does the possible redox regulation at mitochondrial MCSs. Given the relationship between the peroxisomal redox state and overall cellular redox balance, we investigated the role of GDAP1 in peroxisomal function and mitochondrial MCSs maintenance by using high-resolution microscopy, live cell imaging with pH-sensitive fluorescent probes, and transcriptomic and lipidomic analyses in the Gdap1-/- mice and patient-derived fibroblasts. We demonstrate that GDAP1 deficiency disrupts mitochondria-peroxisome MCSs and leads to peroxisomal abnormalities, which are reversible upon pharmacological activation of PPARγ or glutathione supplementation. These results identify GDAP1 as a new tether of mitochondria-peroxisome MCSs that maintain peroxisomal number and integrity. The supply of glutathione (GSH-MEE) or GDAP1 overexpression suffices to rescue these MCSs. Furthermore, GDAP1 may regulate the redox state within the microdomain of mitochondrial MCSs, as suggested by decreased pH at mitochondria-lysosome contacts in patient-derived fibroblasts, highlighting the relationship between GDAP1 and redox-sensitive targets. Finally, in vivo analysis of sciatic nerve tissue in Gdap1-/- mice revealed significant axonal structural abnormalities, including nodes of Ranvier disruption and defects in the distribution and morphology of mitochondria, lysosomes, and peroxisomes, emphasizing the importance of GDAP1 in sustaining axon integrity in the peripheral nervous system. Taken together, this study positions GDAP1 as a multifunctional protein that mediates mitochondrial interaction with cellular organelles of diverse functions, contributes to redox state sensing, and helps maintain axonal homeostasis. In addition, we identify PPAR as a novel therapeutic target, based on knowledge of the underlying pathogenetic mechanisms.

DOI: https://doi.org/10.21203/rs.3.rs-5682984/v1
Int J Mol Sci. 2024 Dec 24. pii: 44. [Epub ahead of print]26(1):

ATAD1 Regulates Neuronal Development and Synapse Formation Through Tuning Mitochondrial Function.

Hao-Hao Yan, Jia-Jia He, Chuanhai Fu, Jia-Hui Chen, Ai-Hui Tang.

  Mitochondrial function is essential for synaptic function. ATAD1, an AAA+ protease involved in mitochondrial quality control, governs fission-fusion dynamics within the organelle. However, the distribution and functional role of ATAD1 in neurons remain poorly understood. In this study, we demonstrate that ATAD1 is primarily localized to mitochondria in dendrites and, to a lesser extent, in spines in cultured hippocampal neurons. We found that ATAD1 deficiency disrupts the mitochondrial fission-fusion balance, resulting in mitochondrial fragmentation. This deficiency also impairs dendritic branching, hinders dendritic spine maturation, and reduces glutamatergic synaptic transmission in hippocampal neuron. To further investigate the underlying mechanism, we employed an ATP hydrolysis-deficient mutant of ATAD1 to rescue the neuronal deficits associated with ATAD1 loss. We discovered that the synaptic deficits are independent of the mitochondrial morphology changes but rely on its ATP hydrolysis. Furthermore, we show that ATAD1 loss leads to impaired mitochondrial function, including decreased ATP production, impaired membrane potential, and elevated oxidative stress. In conclusion, our results provide evidence that ATAD1 is crucial for maintaining mitochondrial function and regulating neurodevelopment and synaptic function.

Keywords:  ATAD1; mitochondrial dysfunction; neuronal development; synapse formation

DOI:  https://doi.org/10.3390/ijms26010044
Brain Commun. 2025 ;7(1): fcae470

Complex I deficiency remains the most frequent cause of Leigh syndrome spectrum.

Shamima Rahman.

This scientific commentary refers to 'Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment', by Kaiyrzhanov et al. (https://doi.org/10.1093/braincomms/fcae453).

DOI: https://doi.org/10.1093/braincomms/fcae470
Acta Physiol (Oxf). 2025 Feb;241(2): e14283

Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.

Yiyi Zhu, Alexei Verkhratsky, Hui Chen, Chenju Yi.

  The blood-brain barrier (BBB) is a highly selective, semipermeable barrier critical for maintaining brain homeostasis. The BBB regulates the transport of essential nutrients, hormones, and signaling molecules between the bloodstream and the central nervous system (CNS), while simultaneously protecting the brain from potentially harmful substances and pathogens. This selective permeability ensures that the brain is nourished and shielded from toxins. An exception to this are brain regions, such as the hypothalamus and circumventricular organs, which are irrigated by fenestrated capillaries, allowing rapid and direct response to various blood components. We overview the metabolic functions of the BBB, with an emphasis on the impact of altered glucose metabolism and insulin signaling on BBB in the pathogenesis of neurodegenerative diseases. Notably, endothelial cells constituting the BBB exhibit distinct metabolic characteristics, primarily generating ATP through aerobic glycolysis. This occurs despite their direct exposure to the abundant oxygen in the bloodstream, which typically supports oxidative phosphorylation. The effects of insulin on astrocytes, which form the glial limitans component of the BBB, show a marked sexual dimorphism. BBB nutrient sensing in the hypothalamus, along with insulin signaling, regulates systemic metabolism. Insulin modifies BBB permeability by regulating the expression of tight junction proteins, angiogenesis, and vascular remodeling, as well as modulating blood flow in the brain. The disruptions in glucose and insulin signaling are particularly evident in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where BBB breakdown accelerates cognitive decline. This review highlights the critical role of normal glucose metabolism and insulin signaling in maintaining BBB functionality and investigates how disruptions in these pathways contribute to the onset and progression of neurodegenerative diseases.

Keywords:  Alzheimer's disease; Huntington's disease; Parkinson's disease; amyotrophic lateral sclerosis; fenestrated capillaries; glucose transporter; insulin resistance; neurodegeneration

DOI:  https://doi.org/10.1111/apha.14283
World Psychiatry. 2025 Feb;24(1): 47-49

Past, present and future of research on brain energy metabolism in bipolar disorder.

Michael Berk, Ken Walder, Jee Hyun Kim.

DOI: https://doi.org/10.1002/wps.21266
EMBO J. 2025 Jan 13.

Glycogen synthase GYS1 overactivation contributes to glycogen insolubility and malto-oligoglucan-associated neurodegenerative disease.

Silvia Nitschke, Alina P Montalbano, Megan E Whiting, Brandon H Smith, Neije Mukherjee-Roy, Charlotte R Marchioni, Mitchell A Sullivan, Xiaochu Zhao, Peixiang Wang, Howard Mount, Mayank Verma, Berge A Minassian, Felix Nitschke.

  Polyglucosans are glycogen molecules with overlong chains, which are hyperphosphorylated in the neurodegenerative Lafora disease (LD). Brain polyglucosan bodies (PBs) cause fatal neurodegenerative diseases including Lafora disease and adult polyglucosan body disease (ABPD), for which treatments, biomarkers, and good understanding of their pathogenesis are currently missing. Mutations in the genes for the phosphatase laforin or the E3 ubiquitin ligase malin can cause LD. By depleting PTG, an activator of the glycogen chain-elongating enzyme glycogen synthase (GYS1), in laforin- and malin-deficient LD mice, we show that abnormal glycogen chain lengths and not hyperphosphorylation underlie polyglucosan formation, and that polyglucosan bodies induce neuroinflammation. We provide evidence indicating that a small pool of overactive GYS1 contributes to glycogen insolubility in LD and APBD. In contrast to previous findings, metabolomics experiments using in situ-fixed brains reveal only modest metabolic changes in laforin-deficient mice. These changes are not replicated in malin-deficient or APBD mice, and are not normalized in rescued LD mice. Finally, we identify a pool of metabolically volatile malto-oligoglucans as a polyglucosan body- and neuroinflammation-associated brain energy source, and promising candidate biomarkers for LD and APBD, including malto-oligoglucans and the neurodegeneration marker CHI3L1/YKL40.

Keywords:  Adult Polyglucosan Body Disease; Biomarkers; Glycogen; Lafora Disease; Neuroinflammation

DOI:  https://doi.org/10.1038/s44318-024-00339-3
Food Sci Nutr. 2025 Jan;13(1): e4767

Long-Term Creatine Supplementation Improves Cognitive and Hippocampal Structural Plasticity Impairments in a D-Gal-Induced Aging Model via Increasing CK-BB Activity in the Brain.

Zhu Zhu, Hantao Zhang, Qianlin Li, Xu Han, Tiantian Wang, Wenjing Zhang, Feiyan Chen, Ling Gu, Qi Yao, Lin Chen, Yunan Zhao.

  Creatine (Cr) is recognized for its role in enhancing cognitive functions through the phosphocreatine (pCr)-creatine kinase system involved in brain energy homeostasis. It is reversibly converted into pCr by creatine kinase (CK). A brain-specific isoform of CK, known as CK-BB, is implicated in the brain's energy metabolism. The objective of this research is to ascertain the impact of Cr supplementation on learning and memory skills as well as on structural synaptic plasticity, by modulating CK-BB. First, we utilized various concentrations of D-galactose (D-gal) to create an aging mouse model. Our findings indicated that D-gal injections at 100 and 1000 mg/kg could lead to cognitive decline, oxidative stress, and damage to structural synaptic plasticity. CK-BB expression and its activity were reduced at least by approximately 20% in mice injected with 100 and 1000 mg/kg D-gal compared with control group. Next, an adeno-associated virus directed against CKB was employed to reduce CK-BB levels by 34% in the brain. The reduction of CK-BB in the brain resulted in deficits in learning and memory, oxidative stress, and morphological harm to the hippocampal spines of mice. Finally, the diet of the D-gal-induced aging model was enriched with 3% Cr. Mice that received 3% Cr supplementation exhibited a 36% increase in CK-BB activity and a 14.3% increase in CK-BB expression following prolonged D-gal administration. In addition, Cr supplementation mitigated the cognitive impairment, oxidative stress, and hippocampal structural plasticity damage caused by chronic D-gal injections. Overall, our study revealed that CK-BB has a critical role in mediating structural plasticity in D-gal-induced cognitive impairment. Moreover, it showed that supplementary Cr could serve as a potent neuroprotective substance, preventing or delaying the course of age-related cognitive deficits.

Keywords:  D‐galactose; cognitive impairment; creatine kinase BB; creatine supplementation; structural plasticity

DOI:  https://doi.org/10.1002/fsn3.4767
Nutrients. 2024 Dec 25. pii: 31. [Epub ahead of print]17(1):

Ketogenic Diet as a Nutritional Metabolic Intervention for Obsessive-Compulsive Disorder: A Narrative Review.

Astrid Lounici, Ana Iacob, Katarzyna Hongler, Melina A Mölling, Maria Drechsler, Luca Hersberger, Shebani Sethi, Undine E Lang, Timur Liwinski.

  The substantial evidence supporting the ketogenic diet (KD) in epilepsy management has spurred research into its effects on other neurological and psychiatric conditions. Despite differences in characteristics, symptoms, and underlying mechanisms, these conditions share common pathways that the KD may influence. The KD reverses metabolic dysfunction. Moreover, it has been shown to support neuroprotection through mechanisms such as neuronal energy support, inflammation reduction, amelioration of oxidative stress, and reversing mitochondrial dysfunction. The adequate intake of dietary nutrients is essential for maintaining normal brain functions, and strong evidence supports the role of nutrition in the treatment and prevention of many psychiatric and neurological disorders. Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition marked by persistent, distressing thoughts or impulses (obsessions) and repetitive behaviors performed in response to these obsessions (compulsions). Recent studies have increasingly examined the role of nutrition and metabolic disorders in OCD. This narrative review examines current evidence on the potential role of the KD in the treatment of OCD. We explore research on the KD's effects on psychiatric disorders to assess its potential relevance for OCD treatment. Additionally, we identify key gaps in the preclinical and clinical research that warrant further study in applying the KD as a metabolic therapy for OCD.

Keywords:  ketogenic diet; metabolic psychiatry; metabolic syndrome; nutritional therapy; obsessive–compulsive disorder

DOI:  https://doi.org/10.3390/nu17010031
Sci Rep. 2025 Jan 16. 15(1): 2138

Identification of a metabolic brain network characterizing essential tremor.

Solange Volnov, Hamzah Baagil, Oliver Winz, Hans-Juergen Kaiser, Sanne Katherina Meles, Joerg Bernhard Schulz, Kathrin Reetz, Felix Manuel Mottaghy, Florian Holtbernd.

  The neuronal correlate of tremor genesis and cognitive function in essential tremor (ET) and its modulation by deep brain stimulation (DBS) are poorly understood. To explore the underlying metabolic topography of motor and cognitive symptoms, sixteen ET patients (age 63.6 ± 49.1 years) and 18 healthy controls (HC) (61.1 ± 6.3 years) underwent tremor and cognitive assessments and18F-fluorodeoxyglucose PET of the brain. Multivariate spatial covariance analysis was applied for identifying ET related metabolic brain networks. For network validation and to explore DBS effects, 8 additional ET patients (68.1 ± 8.2 years) treated with DBS were assessed in both the ON and OFF state, respectively. The ET related metabolic spatial covariance pattern (ETRP) was characterized by relatively increased metabolism in the cerebellum, brainstem, and temporo-occipital cortices, accompanied by relative metabolic decreases mainly in fronto-temporal and motor cortices. Network expression showed inverse correlations with tremor severity and disease duration and positive correlations with cognitive dysfunction. DBS substantially alleviated tremor, but had only marginal effects on cognitive performance. There were no significant DBS effects on ETRP expression at the group level, but all but one subject showed higher scores in the ON state. Our findings suggest ET is characterized by an abnormal brain network associated with disease phenotype.

Keywords:  Brain metabolism; Deep brain stimulation; Essential tremor; FDG PET; Spatial covariance analysis

DOI:  https://doi.org/10.1038/s41598-024-82069-4
Neuroimage. 2025 Jan 08. pii: S1053-8119(25)00015-1. [Epub ahead of print] 121015

Exploring In Vivo Human Brain Metabolism at 10.5 T: Initial Insights from MR Spectroscopic Imaging.

Lukas Hingerl, Bernhard Strasser, Simon Schmidt, Korbinian Eckstein, Guglielmo Genovese, Edward J Auerbach, Andrea Grant, Matt Waks, Andrew Wright, Philipp Lazen, Alireza Sadeghi-Tarakameh, Gilbert Hangel, Fabian Niess, Yigitcan Eryaman, Gregor Adriany, Gregory Metzger, Wolfgang Bogner, Małgorzata Marjańska.

   INTRODUCTION: Ultra-high-field magnetic resonance (MR) systems (7 T and 9.4 T) offer the ability to probe human brain metabolism with enhanced precision. Here, we present the preliminary findings from 3D MR spectroscopic imaging (MRSI) of the human brain conducted with the world's first 10.5 T whole-body MR system.
METHODS: Employing a custom-built 16-channel transmit and 80-channel receive MR coil at 10.5 T, we conducted MRSI acquisitions in six healthy volunteers to map metabolic compounds in the human cerebrum in vivo. Three MRSI protocols with different matrix sizes and scan times (4.4×4.4×4.4 mm³: 10 min, 3.4×3.4×3.4 mm³: 15 min, and 2.75×2.75×2.75 mm³: 25 min) were tested. Concentric ring trajectories were utilized for time-efficient encoding of a spherical 3D k-space with ∼4 kHz spectral bandwidth. B0/B1 shimming was performed based on respective field mapping sequences and anatomical T1-weighted MRI were obtained.
RESULTS: By combining the benefits of an ultra-high-field system with the advantages of free-induction-decay (FID-)MRSI, we present the first metabolic maps acquired at 10.5 T in the healthy human brain at both high (voxel size of 4.4³ mm³) and ultra-high (voxel size of 2.75³ mm³) isotropic spatial resolutions. Maps of 13 metabolic compounds (aspartate, choline compounds and creatine + phosphocreatine, γ-aminobutyric acid (GABA), glucose, glutamine, glutamate, glutathione, myo-inositol, scyllo-inositol, N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), taurine) and macromolecules were obtained individually. The spectral quality was outstanding in the parietal and occipital lobes, but lower in other brain regions such as the temporal and frontal lobes. The average total NAA (tNAA = NAA + NAAG) signal-to-noise ratio over the whole volume of interest was 12.1±8.9 and the full width at half maximum of tNAA was 24.7±9.6 Hz for the 2.75×2.75×2.75 mm³ resolution. The need for an increased spectral bandwidth in combination with spatio-spectral encoding imposed significant challenges on the gradient system, but the FID approach proved very robust to field inhomogeneities of ∆B0 = 45±38 Hz (frequency offset ± spatial STD) and B1+ = 65±11° within the MRSI volume of interest.
DISCUSSION: These preliminary findings highlight the potential of 10.5 T MRSI as a powerful imaging tool for probing cerebral metabolism. By providing unprecedented spatial and spectral resolution, this technology could offer a unique view into the metabolic intricacies of the human brain, but further technical developments will be necessary to optimize data quality and fully leverage the capabilities of 10.5 T MRSI.

Keywords:  10.5 tesla; MRSI; cerebral metabolism; concentric ring trajectories; spatio-spectral encoding; ultra-high-field MRI

DOI:  https://doi.org/10.1016/j.neuroimage.2025.121015
bioRxiv. 2025 Jan 03. pii: 2025.01.02.629779. [Epub ahead of print]

Noncanonical PI(4,5)P2 coordinates lysosome positioning through cholesterol trafficking.

Ryan M Loughran, Gurpreet K Arora, Jiachen Sun, Alicia Llorente, Sophia Crabtree, Kyanh Ly, Ren-Li Huynh, Wonhwa Cho, Brooke M Emerling.

In p53-deficient cancers, targeting cholesterol metabolism has emerged as a promising therapeutic approach, given that p53 loss dysregulates sterol regulatory element-binding protein 2 (SREBP-2) pathways, thereby enhancing cholesterol biosynthesis. While cholesterol synthesis inhibitors such as statins have shown initial success, their efficacy is often compromised by the development of acquired resistance. Consequently, new strategies are being explored to disrupt cholesterol homeostasis more comprehensively by inhibiting its synthesis and intracellular transport. In this study, we investigate a previously underexplored function of PI5P4Ks, which catalyzes the conversion of PI(5)P to PI(4,5)P 2 at intracellular membranes. Our findings reveal that PI5P4Ks play a key role in facilitating lysosomal cholesterol transport, regulating lysosome positioning, and sustaining growth signaling via the mTOR pathway. While PI5P4Ks have previously been implicated in mTOR signaling and tumor proliferation in p53-deficient contexts, this work elucidates an upstream mechanism that unifies these earlier observations.

DOI: https://doi.org/10.1101/2025.01.02.629779
Arq Neuropsiquiatr. 2025 Jan;83(1): 1-13

The role of lipid metabolism in cognitive impairment.

Meifang Xu, Liyuan Wang, Yun Meng, Guiqiong Kang, Qing Jiang, Tao Yan, Fengyuan Che.

Alzheimer's disease (AD), diabetic cognitive impairment (DCI), and vascular dementia (VD) are considered the most common causes of severe cognitive impairment in clinical practice. Numerous factors can influence their progression, and many studies have recently revealed that metabolic disorders play crucial roles in the progression of cognitive impairment. Mounting evidence indicate that the regulation of lipid metabolism is a major factor in maintaining brain homeostasis. Generally, abnormalities in lipid metabolism can affect amyloid-beta (Aβ) deposition, tau hyperphosphorylation, and insulin resistance through lipid metabolic signaling cascades; affect the neuronal membrane structure, neurotransmitter synthesis and release; and promote synapse growth, which can impact neural signal transmission and exacerbate disease progression in individuals with cognitive impairment, including AD, DCI, and VD. Moreover, apolipoprotein E (APOE), a key protein in lipid transport, is involved in the occurrence and development of the aforementioned diseases by regulating lipid metabolism. The present article mainly discusses how lipid metabolic disorders in the brain microenvironment are involved in regulating the progression of cognitive impairment, and it explores the regulatory effects of targeting the key lipid transport protein APOE in the context of the role of lipid metabolism in the common pathogenesis of three diseases-Aβ deposition, tau hyperphosphorylation, and insulin resistance-which will help elucidate the potential of targeting lipid metabolism for the treatment of cognitive impairment.

DOI: https://doi.org/10.1055/s-0044-1792097
Mol Genet Metab. 2025 Jan;pii: S1096-7192(24)00891-6. [Epub ahead of print]144(1): 109007

Mitochondrial HMG-CoA synthase deficiency.

Bram Decru, Marine Lys, Kobe Truijens, Nathalie Mercier, Jean Papadopoulos, Daisy Rymen, Dominique Roland, Joseph P Dewulf, Pieter Vermeersch.

  Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) deficiency is a rare, potentially life-threatening autosomal recessive disorder resulting from mutations in the HMGCS2 gene, leading to impaired ketogenesis. We systematically reviewed the clinical presentations, biochemical and genetic abnormalities in 93 reported cases and 2 new patients diagnosed based on biochemical findings. Reported onset ages ranged from 3 months to 6 years, mostly before the age of 3. Children younger than one year old are more prone to a severe clinical course. In most patients, the initial metabolic decompensation occurs after an episode of gastroenteritis or gastroenteritis-like symptoms. Other commonly observed symptoms during the first clinical episode included poor intake, altered consciousness, dyspnea, seizures and hepatomegaly. Severity was correlated with the number of truncating mutations. Most patients presented with acute metabolic decompensation with hypoglycemia, dicarboxyluria and inadequate ketonuria. Dicarboxylic acid levels were elevated in 54/56 cases. The organic acid 4-hydroxy-6-methyl-2-pyrone (4HMP) was detected in 33/35 urine samples taken during the acute episodes, but typically only retrospectively. The plasma C2/C0 acylcarnitine ratio was abnormal in 16/18 (88.9 %) of acute plasma samples, but only in 2/6 (33 %) of DBS samples. Other metabolites that have been reported are hydroxyhexenoic acid, 3,5-dihydroxyhexanoic (1,5 lactone), glutaric acidand 3-OH-isovaleric acid. Laboratories should look for 4HMP in urinary organic acid analysis and an increased plasma C2/C0 acylcarnitine ratio to facilitate the diagnosis of HMGCS2 deficiency, especially in cases of metabolic decompensation with dicarboxyluria without adequate ketonuria.

Keywords:  4-hydroxy-6-methyl-2-pyrone; HMGCS2; Hypoketotic hypoglycemia; Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase

DOI:  https://doi.org/10.1016/j.ymgme.2024.109007
bioRxiv. 2025 Jan 03. pii: 2025.01.02.631150. [Epub ahead of print]

Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in H3K27M-mutant gliomas.

Georgios Batsios, Céline Taglang, Suresh Udutha, Anne Marie Gillespie, Simon P Robinson, Timothy Phoenix, Sabine Mueller, Sriram Venneti, Carl Koschmann, Pavithra Viswanath.

Oncogenes hyperactive lactate production, but the mechanisms by which lactate facilitates tumor growth are unclear. Here, we demonstrate that lactate is essential for nucleotide biosynthesis in pediatric diffuse midline gliomas (DMGs). The oncogenic histone H3K27M mutation upregulates phosphoglycerate kinase 1 (PGK1) and drives lactate production from [U- 13 C]-glucose in DMGs. Lactate activates the nucleoside diphosphate kinase NME1 via lactylation and promotes the synthesis of nucleoside triphosphates essential for tumor proliferation. Importantly, we show that this mechanistic link between glycolysis and nucleotide biosynthesis provides a unique opportunity for deuterium metabolic imaging of DMGs. Spatially mapping 2 H-lactate production from [6,6- 2 H]-glucose allows visualization of the metabolically active tumor lesion and provides an early readout of response to standard-of-care radiation and targeted therapy that precedes extended survival and reflects pharmacodynamic alterations at the tissue level in preclinical DMG models in vivo at clinical field strength (3T). In essence, we have identified an H3K27M-lactate-NME1 axis that promotes DMG proliferation and facilitates non-invasive metabolic imaging of DMGs.
STATEMENT OF SIGNIFICANCE: This study establishes a role for lactate in driving nucleotide biosynthesis in DMGs. Importantly, imaging lactate production from glucose using DMI provides a readout of tumor proliferation and early response to therapy in clinically relevant DMG models. Our studies lay the foundation for precision metabolic imaging of DMG patients.

DOI: https://doi.org/10.1101/2025.01.02.631150
Molecules. 2024 Dec 28. pii: 71. [Epub ahead of print]30(1):

Molecular Mechanisms Linking Omega-3 Fatty Acids and the Gut-Brain Axis.

Anna Zinkow, Wojciech Grodzicki, Malwina Czerwińska, Katarzyna Dziendzikowska.

  The gut-brain axis (GBA) is a complex communication network connecting the gastrointestinal tract (GIT) and the central nervous system (CNS) through neuronal, endocrine, metabolic, and immune pathways. Omega-3 (n-3) fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are crucial food components that may modulate the function of this axis through molecular mechanisms. Derived mainly from marine sources, these long-chain polyunsaturated fatty acids are integral to cell membrane structure, enhancing fluidity and influencing neurotransmitter function and signal transduction. Additionally, n-3 fatty acids modulate inflammation by altering eicosanoid production, reducing proinflammatory cytokines, and promoting anti-inflammatory mediators. These actions help preserve the integrity of cellular barriers like the intestinal and blood-brain barriers. In the CNS, EPA and DHA support neurogenesis, synaptic plasticity, and neurotransmission, improving cognitive functions. They also regulate the hypothalamic-pituitary-adrenal (HPA) axis by reducing excessive cortisol production, associated with stress responses and mental health disorders. Furthermore, n-3 fatty acids influence the composition and function of the gut microbiota, promoting beneficial bacterial populations abundance that contribute to gut health and improve systemic immunity. Their multifaceted roles within the GBA underscore their significance in maintaining homeostasis and supporting mental well-being.

Keywords:  cognitive function; docosahexaenoic acid (DHA); eicosapentaenoic acid (EPA); gut microbiota; gut–brain axis (GBA); hypothalamic–pituitary–adrenal (HPA) axis; inflammation; omega-3 (n-3) fatty acids

DOI:  https://doi.org/10.3390/molecules30010071
BBA Adv. 2025 ;7 100134

Phosphorylation of N-glycans in the brain: The case for a non-canonical pathway?

Lucija Sironić, Nikol Mraz, Gordan Lauc, Thomas S Klarić.

  Asparagine-linked glycosylation (N-glycosylation) is a common co- and post-translational modification that refers to the addition of complex carbohydrates, called N-linked glycans (N-glycans), to asparagine residues within defined sequons of polypeptide acceptors. Some N-glycans can be modified by the addition of phosphate moieties to their monosaccharide residues, thus forming phospho-N-glycans (PNGs). The most prominent such carbohydrate modification is mannose-6-phosphate (M6P) which plays a well-established role in trafficking of acid hydrolases to lysosomes. However, comparatively little is known about potential alternative types of glycan phosphorylation, particularly when it comes to the brain which is especially rich in phosphorylated oligosaccharides. Combining data from the literature and novel insights derived from our own analyses of published datasets, here we present what is currently known about PNGs in the brain and the glycoproteins they modify. We show that brain PNGs exhibit several distinctive features that don't completely align with our current understanding of the canonical M6P pathway. Furthermore, we demonstrate that there are numerous differences in the way that lysosomal and non-lysosomal neural glycoproteins are modified by PNGs. Based on these observations, we put forward the hypothesis that, in addition to the conventional M6P pathway, the brain employs an alternative oligosaccharide phosphorylation mechanism for the modification of a discrete set of glycoproteins. Here we examine the evidence underpinning this hypothesis and discuss the implications that it raises. Overall, our work suggests that phosphorylation of N-glycans in the brain may be more complex and more diverse than previously recognised.

Keywords:  Brain; Lysosome; M6P; N-glycan; N-glycosylation; Oligomannose; Phosphoglycoproteins; Phosphorylation

DOI:  https://doi.org/10.1016/j.bbadva.2024.100134
Neurochem Int. 2025 Jan 09. pii: S0197-0186(24)00254-7. [Epub ahead of print]183 105927

The role of mitochondrial remodeling in neurodegenerative diseases.

Duanqin Guan, Congmin Liang, Dongyan Zheng, Shizhen Liu, Jiankun Luo, Ziwei Cai, He Zhang, Jialong Chen.

  Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.

Keywords:  Biosynthesis; Mitochondrial quality control; Mitochondrial remodeling; Neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.neuint.2024.105927
Expert Rev Proteomics. 2025 Jan 15. 1-15

Interaction and regulation of the mitochondrial proteome - in health and disease.

Johan Palmfeldt.

   INTRODUCTION: Mitochondria contain multiple pathways including energy metabolism and several signaling and synthetic pathways. Mitochondrial proteomics is highly valuable for studying diseases including inherited metabolic disorders, complex and common disorders like neurodegeneration, diabetes, and cancer, since they all to some degree have mitochondrial underpinnings.
AREAS COVERED: The main mitochondrial functions and pathways are outlined, and systematic protein lists are presented. The main energy metabolic pathways are as follows: iron-sulfur cluster synthesis, one carbon metabolism, catabolism of hydrogen sulfide, kynurenines and reactive oxygen species (ROS), and others, described with the aim of laying a foundation for systematic mitochondrial pathway analysis based on proteomics data. The links of the proteins and pathways to functional effects and diseases are discussed. The disease examples are focussed on inherited metabolic disorders, cancer, neurological, and cardiovascular disorders.
EXPERT OPINION: To elucidate the role of mitochondria in health and disease, there is a need for comprehensive proteomics analyses with stringent, systematic data treatment for proper interpretation of mitochondrial pathway data. In that way, comprehensive hypothesis-based research can be performed based on proteomics data.

Keywords:  Mitochondrion; NAD; biomarker panels; kynurenine; metabolic disorders; oxidative phosphorylation; proteomics; stress response

DOI:  https://doi.org/10.1080/14789450.2025.2451704
Pediatr Neurol. 2024 Dec 25. pii: S0887-8994(24)00418-1. [Epub ahead of print]164 7-9

Progressive Loss of Cerebral Structures in ALG11-Related Congenital Disorder Glycosylation.

Olivier Fortin, Gilbert Vezina, David M Steinhorn, Sarah B Mulkey.

   BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of metabolic disorders related to dysfunctional glycoprotein and glycolipid biosynthesis. ALG11-related CDG is a rare member of this group, characterized by severe neurodevelopmental impairment, progressive microcephaly, sensorineural hearing loss, and epilepsy. The objective of this report is to provide an update on the phenotype and brain magnetic resonance imaging (MRI) at age seven years for a patient initially described in early infancy with fetal brain disruption sequence.
METHODS: We provide an updated detailed clinical description of a seven-year-old male with ALG-11 CDG who underwent brain MRI at age seven years.
RESULTS: Brain MRI at age seven years showed significant disease progression compared to the neonatal brain MRI. There was near complete loss of cerebral hemispheres, severe cerebellar atrophy, and decreased volume of the brainstem. The prior brain MRI (done at six weeks of age) had shown severe supratentorial volume loss but a relatively preserved cerebellum and brainstem at that time.
CONCLUSIONS: Reports on the natural history of rare conditions are important to improve our understanding of these conditions. ALG11-CDG is associated with atrophy and eventual vanishing of supratentorial brain structures, and infratentorial brain structures later in the disease process. The involvement of a pediatric palliative care service is a valuable adjunct to assist with symptom management and family support for these complex progressive conditions.

Keywords:  Brain atrophy; Congenital disorders of glycosylation; Fetal neurology; Neurogenetics; Neuroimaging; Palliative care

DOI:  https://doi.org/10.1016/j.pediatrneurol.2024.12.009
Crit Care. 2025 Jan 15. 29(1): 26

Metabolomic in severe traumatic brain injury: exploring primary, secondary injuries, diagnosis, and severity.

Canadian Biobank and Database for Traumatic Brain Injury (CanTBI) study investigators

   BACKGROUND: Traumatic brain injury (TBI) is a major public health concern worldwide, contributing to high rates of injury-related death and disability. Severe traumatic brain injury (sTBI), although it accounts for only 10% of all TBI cases, results in a mortality rate of 30-40% and a significant burden of disability in those that survive. This study explored the potential of metabolomics in the diagnosis of sTBI and explored the potential of metabolomics to examine probable primary and secondary brain injury in sTBI.
METHODS: Serum samples from 59 adult patients with sTBI and 35 age- and sex-matched orthopedic injury controls were subjected to quantitative metabolomics, including proton nuclear magnetic resonance (1H-NMR) and direct infusion/liquid chromatography-tandem mass spectrometry (DI/LC-MS/MS), to identify and quantify metabolites on days 1 and 4 post-injury. In addition, we used advanced analytical methods to discover metabo-patterns associated with sTBI diagnosis and those related to probable primary and secondary brain injury.
RESULTS: Our results showed different serum metabolic profiles between sTBI and orthopedic injury (OI) controls, with significant changes in measured metabolites on day 1 and day 4 post-brain injury. The number of altered metabolites and the extent of their change were more pronounced on day 4 as compared to day 1 post-injury, suggesting an evolution of mechanisms from primary to secondary brain injury. Data showed high sensitivity and specificity in separating sTBI from OI controls for diagnosis. Energy-related metabolites such as glucose, pyruvate, lactate, mannose, and polyamine metabolism metabolites (spermine and putrescine), as well as increased acylcarnitines and sphingomyelins, occurred mainly on day 1 post-injury. Metabolites of neurotransmission, catecholamine, and excitotoxicity mechanisms such as glutamate, phenylalanine, tyrosine, and branched-chain amino acids (BCAAs) increased to a greater degree on day 4. Further, there was an association of multiple metabolites, including acylcarnitines (ACs), lysophosphatidylcholines (LysoPCs), glutamate, and phenylalanine, with injury severity at day 4, while lactate, glucose, and pyruvate correlated with injury severity on day 1.
CONCLUSION: The results demonstrate that serum metabolomics has diagnostic potential for sTBI and may reflect molecular mechanisms of primary and secondary brain injuries when comparing metabolite profiles between day 1 and day 4 post-injury. These early changes in serum metabolites may provide insight into molecular pathways or mechanisms of primary injury and ongoing secondary injuries, revealing potential therapeutic targets for sTBI. This work also highlights the need for further research and validation of sTBI metabolite biomarkers in a larger cohort.

Keywords:  Metabolites; Metabolomics; Primary and secondary injury; sTBI

DOI:  https://doi.org/10.1186/s13054-025-05258-1
Methods Mol Biol. 2025 ;2891 131-152

Quantitative Lipidomics of Biological Samples Using Supercritical Fluid Chromatography Mass Spectrometry.

Hiroaki Takeda, Yoshihiro Izumi, Takeshi Bamba.

  Lipidomics has attracted attention in the discovery of unknown biomolecules and for capturing the changes in metabolism caused by genetic and environmental factors in an unbiased manner. However, obtaining reliable lipidomics data, including structural diversity and quantification data, is still challenging. Supercritical fluid chromatography (SFC) is a suitable technique for separating lipid molecules with high throughput and separation efficiency. Here, we describe a quantitative lipidomics method using SFC coupled with mass spectrometry. This technique is suitable for characterizing the structural diversity of lipids (e.g., phospholipids, sphingolipids, glycolipids, and glycerolipids) with high quantitative accuracy to understand their biological functions.

Keywords:  Cells; Extracellular vesicles; Glycerolipids; Glycolipids; Lipidomics; Lipoproteins; Liquid-liquid extraction; Mass spectrometry; Organs; Phospholipids; Plasma; Quantitative analysis; Sphingolipids; Supercritical fluid chromatography; Tissues

DOI:  https://doi.org/10.1007/978-1-0716-4334-1_7
Mol Neurodegener. 2025 Jan 15. 20(1): 6

SIRT2 and ALDH1A1 as critical enzymes for astrocytic GABA production in Alzheimer's disease.

Mridula Bhalla, Jinhyeong Joo, Daeun Kim, Jeong Im Shin, Yongmin Mason Park, Yeon Ha Ju, Uiyeol Park, Seonguk Yoo, Seung Jae Hyeon, Hyunbeom Lee, Junghee Lee, Hoon Ryu, C Justin Lee.

   BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disease with drastically altered astrocytic metabolism. Astrocytic GABA and H2O2 are associated with memory impairment in AD and synthesized through the Monoamine Oxidase B (MAOB)-mediated multi-step degradation of putrescine. However, the enzymes downstream to MAOB in this pathway remain unidentified.
METHODS: Using transcriptomics analysis, we identified two candidate enzymes, Aldehyde Dehydrogenase 1 family member A1 (ALDH1A1) and Sirtuin 2 (SIRT2) for the steps following MAOB in the astrocytic GABA production pathway. We used immunostaining, metabolite analysis and electrophysiology, both in vitro and in vivo, to confirm the participation of these enzymes in astrocytic GABA production. We checked for the presence of SIRT2 in human AD patients as well as the mouse model APP/PS1 and finally, we selectively ablated SIRT2 in the astrocytes of APP/PS1 mice to observe its effects on pathology.
RESULTS: Immunostaining, metabolite analysis, and electrophysiology recapitulated the participation of ALDH1A1 and SIRT2 in GABA production. Inhibition of SIRT2 reduced the production of astrocytic GABA but not H2O2, a key molecule in neurodegeneration. Elevated expression of these enzymes was found in hippocampal astrocytes of AD patients and APP/PS1 mice. Astrocyte-specific gene-silencing of SIRT2 in APP/PS1 mice restored GABA production and partially improved memory function.
CONCLUSIONS: Our study is the first to identify the specific role of SIRT2 in reactive astrogliosis and determine the specific pathway and metabolic step catalyzed by the enzyme. We determine the partial, yet significant role of ALDH1A1 in this process, thereby highlighting 2 new players the astrocytic GABA production pathway. Our findings therefore, offer SIRT2 as a new tool to segregate GABA from H2O2 production, aiding future research in neurodegenerative diseases.

Keywords:  ALDH1A1; Alzheimer’s disease; Amyloid-beta; GABA; Reactive astrocytes; SIRT2

DOI:  https://doi.org/10.1186/s13024-024-00788-8
Am J Physiol Endocrinol Metab. 2025 Jan 13.

Constitutive loss of kynurenine-3-monooxygenase changes circulating kynurenine metabolites without affecting systemic energy metabolism.

Kyle D Dumont, Paulo R Jannig, Margareta Porsmyr-Palmertz, Jorge L Ruas.

  Kynurenic acid (KYNA) and quinolinic acid (QUIN) are metabolites of the kynurenine pathway of tryptophan degradation with opposing biological activities in the central nervous system. In the periphery, KYNA is known to positively affect metabolic health, whereas the effects of QUIN remain less explored. Interestingly, metabolic stressors, including exercise and obesity, differentially change the balance between circulating KYNA and QUIN. Here, we hypothesized that chronically elevated levels of circulating KYNA and reduced levels of QUIN would manifest as differences in whole-body energy metabolism. To test this, we used a mouse model lacking the enzyme kynurenine 3-monooxygenase (KMO), thus shunting kynurenine away from QUIN synthesis and towards KYNA production. KMO-deficient and wild-type littermate male and female mice were evaluated under chow and high-fat diets. Comprehensive kynurenine pathway metabolite profiling in plasma showed that the loss of KMO elicits robust changes in circulating levels of kynurenine metabolites. This included a 45-fold increase in kynurenine, a 26-fold increase in KYNA, and a 99% decrease in QUIN levels, depending on the diet. However, despite these changes, loss of KMO did not significantly impact whole-body energy metabolism or change the transcriptomic profile of subcutaneous adipose tissue on either diet. With KMO inhibitors being considered as therapeutic candidates for various disorders, this work shows that chronic systemic KMO inhibition does not have widespread metabolic effects. Our data also indicates that the beneficial effects of KYNA on metabolism may depend on its acute, intermittent elevation in circulation, akin to transient exercise-induced signals that mediate improved metabolic health.

Keywords:  Adipose tissue; High-fat diet; KMO; Kynurenine monooxygenase; Metabolism; Transcriptomics; Tryptophan-kynurenine metabolites

DOI:  https://doi.org/10.1152/ajpendo.00386.2024