bims-medebr 2023-10-29 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒10‒29
38 papers selected by
Regina F. Fernández, Johns Hopkins University

MALDI-IM-MS Imaging of Brain Sterols and Lipids in a Mouse Model of Smith-Lemli-Opitz Syndrome.
Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function.
Lactate's behavioral switch in the brain: an in-silico model.
Effects of DHA on cognitive dysfunction in aging and Alzheimer's disease: The mediating roles of ApoE.
Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
Mitochondrial modulation with leriglitazone as a potential treatment for Rett syndrome.
Sphingolipid metabolism in brain insulin resistance and neurological diseases.
Identification of Intron Retention in the Slc16a3 Gene Transcript Encoding the Transporter MCT4 in the Brain of Aged and Alzheimer-Disease Model (APPswePS1dE9) Mice.
N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency.
Plasma oxylipin profiles reflect Parkinson's disease stage.
Disrupting astrocyte-neuron lactate transport prevents cocaine seeking after prolonged withdrawal.
The atypical sphingolipid SPB 18:1(14Z);O2 is a biomarker for DEGS1 related hypomyelinating leukodystrophy.
Mitochondrial complex I ROS production and redox signaling in hypoxia.
GM1 ganglioside exerts protective effects against glutamate-excitotoxicity via its oligosaccharide in wild-type and amyotrophic lateral sclerosis motor neurons.
Pantothenate kinase activation restores brain coenzyme A in a mouse model of pantothenate kinase associated neurodegeneration.
Regulation of astrocyte metabolism by mitochondrial translocator protein 18kDa.
The Role of Astrocytic Mitochondria in the Pathogenesis of Brain Ischemia.
Phosphoglycerate kinase 1 is a central leverage point in Parkinson's disease driven neuronal metabolic deficits.
Effects of Neonatal Hypoxic-Ischemic Injury on Brain Sterol Synthesis and Metabolism.
EXPRESS: Cholesterol Deficiency as a Mechanism for Autism: A Valproic Acid Model.
Shared genetic basis informs the roles of polyunsaturated fatty acids in brain disorders.
BDNF and Lactate as Modulators of Hippocampal CA3 Network Physiology.
Drosophila tweety facilitates autophagy to regulate mitochondrial homeostasis and bioenergetics in Glia.
Visualization of accessible cholesterol using a GRAM domain-based biosensor.
The ketone body β-hydroxybutyrate shifts microglial metabolism and suppresses amyloid-β oligomer-induced inflammation in human microglia.
Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.
Sialidase NEU3 action on GM1 ganglioside is neuroprotective in GM1 Gangliosidosis.
A strategic tool to improve the study of molecular determinants of Alzheimer's disease: The role of glyceraldehyde.
Gut microbiota-derived short chain fatty acids act as mediators of the gut-brain axis targeting age-related neurodegenerative disorders: a narrative review.
Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency: Family Impact and Perspectives.
Patient-Derived Cellular Models for Polytarget Precision Medicine in Pantothenate Kinase-Associated Neurodegeneration.
Disrupted brain mitochondrial morphology after in vivo hydrogen sulfide exposure.
Insights on the Correlation between Mitochondrial Dysfunction and the Progression of Parkinson's Disease.
Neonatal Maternal Separation Induces Sexual Dimorphism in Brain Development: The Influence on Amino Acid Levels and Cognitive Disorders.
Loss of Depalmitoylation Disrupts Homeostatic Plasticity of AMPARs in a Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis.
Mitochondrial glutamate transporter SLC25A22 uni-directionally export glutamate for metabolic rewiring in radioresistant glioblastoma.
Lysosomal proteomics reveals mechanisms of neuronal apoE4-associated lysosomal dysfunction.
Untargeted Lipidomic Approach for Studying Different Nervous System Tissues of the Murine Model of Krabbe Disease.

bioRxiv. 2023 Oct 02. pii: 2023.10.02.560415. [Epub ahead of print]

MALDI-IM-MS Imaging of Brain Sterols and Lipids in a Mouse Model of Smith-Lemli-Opitz Syndrome.

Amy Li, Libin Xu.

Smith-Lemli-Opitz syndrome (SLOS) is a neurodevelopmental disorder caused by genetic mutations in the DHCR7 gene, encoding the enzyme 3β-hydroxysterol-Δ 7 -reductase (DHCR7) that catalyzes the last step of cholesterol synthesis. The resulting deficiency in cholesterol and accumulation of its precursor, 7-dehydrocholesterol (7-DHC), have a profound impact on brain development, which manifests as developmental delay, cognitive impairment, and behavioral deficits. To understand how the brain regions are differentially affected by the defective Dhcr7, we aim to map the regional distribution of sterols and other lipids in neonatal brains from a Dhcr7 -KO mouse model of SLOS, using mass spectrometry imaging (MSI). MSI enables spatial localization of biomolecules in situ on the surface of a tissue section, which is particularly useful for mapping the changes that occur within a metabolic disorder such as SLOS, and in an anatomically complex organ such as the brain. In this work, using MALDI-ion mobility (IM)-MSI, we successfully determined the regional distribution of features that correspond to cholesterol, 7-DHC/desmosterol, and the precursor of desmosterol, 7-dehydrodesmosterol, in WT and Dhcr7 -KO mice. Interestingly, we also observed m/z values that match the major oxysterol metabolites of 7-DHC (DHCEO and hydroxy-7-DHC), which displayed similar patterns as 7-DHC. We then identified brain lipids using m/z and CCS at the Lipid Species-level and curated a database of MALDI-IM-MS-derived lipid CCS values. Subsequent statistical analysis of regions-of-interest allowed us to identify differentially expressed lipids between Dhcr7 -KO and WT brains, which could contribute to defects in myelination, neurogenesis, neuroinflammation, and learning and memory in SLOS.

DOI: https://doi.org/10.1101/2023.10.02.560415
Cardiovasc Res. 2023 Oct 26. pii: cvad159. [Epub ahead of print]

Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function.

Maria Borrell-Pages, Aureli Luquero, Gemma Vilahur, Teresa Padró, Lina Badimon.

  OBJECTIVE: There is little information on the regulation of cholesterol homeostasis in the brain. Whether cholesterol crosses the blood-brain barrier is under investigation, but the present understanding is that cholesterol metabolism in the brain is independent from that in peripheral tissues. Lipoprotein receptors from the LDL receptor family (LRPs) have key roles in lipid particle accumulation in cells involved in vascular and cardiac pathophysiology, however, their function on neural cells is unknown.APPROACH AND RESULTS: The expression of LRP5 and components and targets of its downstream signaling pathway, the canonical WNT pathway including β-catenin, LEF1, VEGF, OPN MMP7 and ADAM10 is analyzed in brains of Wt and Lrp5-/- mice and in a neuroblastoma cell line. LRP5 expression is increased in a time-dependent and dose-dependent manner after lipid loading in neuronal cells; however it does not participate in cholesterol homeostasis as shown by intracellular lipid accumulation analyses. Neurons challenged with stausporin and H2O2 display an anti-apoptotic protective role for LRP5.
CONCLUSIONS: We show for the first time that neurons can accumulate intracellular lipids and that lipid uptake is performed mainly by the LDLR while CD36, LRP1, and LRP5 do not play a major role. We also show that LRP5 triggers the canonical WNT pathway in neuronal cells to generate pro-survival signals. Finally we show, that Lrp5-/- mice have maintained expression of LRP5 only in the brain supporting the biological plausible concept of the need of brain LRP5 to elicit pro-survival processes and embryonic viability.

Keywords:  Cholesterol homeostasis; LRP; lipids; neurons

DOI:  https://doi.org/10.1093/cvr/cvad159
J Theor Biol. 2023 Oct 19. pii: S0022-5193(23)00245-X. [Epub ahead of print] 111648

Lactate's behavioral switch in the brain: an in-silico model.

Milad Soltanzadeh, Solenna Blanchard, Jean-Paul Soucy, Habib Benali.

  It is well known that glucose serves as the main energy substrate for the brain, and emerging evidence emphasizes its involvement in both physiological processes and disease (traumatic brain injury, memory, epilepsy, etc.). Furthermore, the usefulness of mathematical modeling in deciphering underlying dynamics of the brain to investigate lactate roles and mechanisms of action has been well established. Here, we analyze a novel mathematical model of brain lactate exchanges between four compartments: neurons, astrocytes, capillaries, and extracellular space. A system of four ordinary differential equations is proposed to explain interactions between these compartments. We first optimize the model's parameters under normal, resting state conditions, and then use it to simulate changes linked to elevated arterial lactate. Our results show that even though increased arterial lactate results in increased uptake by astrocytes and release to the extracellular space, it cannot strongly recover the initial drop in neuronal lactate concentration. Also, we show that the direction of lactate transport between the compartments is influenced by the maximum astrocyte production rate and the transport rate between astrocytes and extracellular space.

Keywords:  Astrocytes; Brain Metabolism; Lactate; Mathematical Modeling; Optimization

DOI:  https://doi.org/10.1016/j.jtbi.2023.111648
Prog Lipid Res. 2023 Oct 25. pii: S0163-7827(23)00046-2. [Epub ahead of print] 101256

Effects of DHA on cognitive dysfunction in aging and Alzheimer's disease: The mediating roles of ApoE.

Xin Zhang, Tian Yuan, Xuhui Chen, Xuebo Liu, Jun Hu, Zhigang Liu.

  The prevalence of Alzheimer's disease (AD) continues to rise due to the increasing aging population. Among the various genetic factors associated with AD, apolipoprotein E (ApoE), a lipid transporter, stands out as the primary genetic risk factor. Specifically, individuals carrying the ApoE4 allele exhibit a significantly higher risk. However, emerging research indicates that dietary factors play a prominent role in modifying the risk of AD. Docosahexaenoic acid (DHA), a prominent ω-3 fatty acid, has garnered considerable attention for its potential to ameliorate cognitive function. The intricate interplay between DHA and the ApoE genotype within the brain, which may influence DHA's utilization and functionality, warrants further investigation. This review meticulously examines experimental and clinical studies exploring the effects of DHA on cognitive decline. Special emphasis is placed on elucidating the role of ApoE gene polymorphism and the potential underlying mechanisms are discussed. These studies suggest that early DHA supplementation may confer benefits to cognitively normal older adults carrying the ApoE4 gene. However, once AD develops, ApoE4 non-carriers may experience greater benefits compared to ApoE4 carriers, although the overall effectiveness of DHA supplementation at this stage is limited. Potential mechanisms underlying these differential effects may include accelerated DHA catabolism in ApoE4 carriers, impaired transport across the blood-brain barrier (BBB), and compromised lipidization and circulatory function in ApoE4 carriers. Thus, the supplementation of DHA may represent a potential intervention strategy aimed at compensating for these deficiencies in ApoE4 carriers prior to the onset of AD.

Keywords:  Alzheimer's disease; Apolipoprotein E; Cognitive dysfunction; Docosahexaenoic acid

DOI:  https://doi.org/10.1016/j.plipres.2023.101256
Redox Biol. 2023 Oct 17. pii: S2213-2317(23)00333-6. [Epub ahead of print]67 102932

Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.

Gerardo G Piroli, Allison M Manuel, Richard S McCain, Holland H Smith, Oliver Ozohanics, Sara Mellid, J Hunter Cox, William E Cotham, Michael D Walla, Alberto Cascón, Attila Ambrus, Norma Frizzell.

  The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the affected regions of the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the existing oxidative phosphorylation (OXPHOS) ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.

Keywords:  Alpha-ketoglutarate dehydrogenase; Complex I; Fumarate; Leigh syndrome; Protein succination; Substrate level phosphorylation

DOI:  https://doi.org/10.1016/j.redox.2023.102932
J Transl Med. 2023 Oct 26. 21(1): 756

Mitochondrial modulation with leriglitazone as a potential treatment for Rett syndrome.

Uliana Musokhranova, Cristina Grau, Cristina Vergara, Laura Rodríguez-Pascau, Clara Xiol, Alba A Castells, Soledad Alcántara, Pilar Rodríguez-Pombo, Pilar Pizcueta, Marc Martinell, Angels García-Cazorla, Alfonso Oyarzábal.

  BACKGROUND: Rett syndrome is a neuropediatric disease occurring due to mutations in MECP2 and characterized by a regression in the neuronal development following a normal postnatal growth, which results in the loss of acquired capabilities such as speech or purposeful usage of hands. While altered neurotransmission and brain development are the center of its pathophysiology, alterations in mitochondrial performance have been previously outlined, shaping it as an attractive target for the disease treatment.METHODS: We have thoroughly described mitochondrial performance in two Rett models, patients' primary fibroblasts and female Mecp2tm1.1Bird-/+ mice brain, discriminating between different brain areas. The characterization was made according to their bioenergetics function, oxidative stress, network dynamics or ultrastructure. Building on that, we have studied the effect of leriglitazone, a PPARγ agonist, in the modulation of mitochondrial performance. For that, we treated Rett female mice with 75 mg/kg/day leriglitazone from weaning until sacrifice at 7 months, studying both the mitochondrial performance changes and their consequences on the mice phenotype. Finally, we studied its effect on neuroinflammation based on the presence of reactive glia by immunohistochemistry and through a cytokine panel.
RESULTS: We have described mitochondrial alterations in Rett fibroblasts regarding both shape and bioenergetic functions, as they displayed less interconnected and shorter mitochondria and reduced ATP production along with increased oxidative stress. The bioenergetic alterations were recalled in Rett mice models, being especially significant in cerebellum, already detectable in pre-symptomatic stages. Treatment with leriglitazone recovered the bioenergetic alterations both in Rett fibroblasts and female mice and exerted an anti-inflammatory effect in the latest, resulting in the amelioration of the mice phenotype both in general condition and exploratory activity.
CONCLUSIONS: Our studies confirm the mitochondrial dysfunction in Rett syndrome, setting the differences through brain areas and disease stages. Its modulation through leriglitazone is a potential treatment for this disorder, along with other diseases with mitochondrial involvement. This work constitutes the preclinical necessary evidence to lead to a clinical trial.

Keywords:  Bioenergetics; Leriglitazone; Metabolic modulation; Mitochondria; Neuroinflammation; Rett syndrome

DOI:  https://doi.org/10.1186/s12967-023-04622-5
Front Endocrinol (Lausanne). 2023 ;14 1243132

Sphingolipid metabolism in brain insulin resistance and neurological diseases.

Meng Mei, Maochang Liu, Yan Mei, Jing Zhao, Yang Li.

  Sphingolipids, as members of the large lipid family, are important components of plasma membrane. Sphingolipids participate in biological signal transduction to regulate various important physiological processes such as cell growth, apoptosis, senescence, and differentiation. Numerous studies have demonstrated that sphingolipids are strongly associated with glucose metabolism and insulin resistance. Insulin resistance, including peripheral insulin resistance and brain insulin resistance, is closely related to the occurrence and development of many metabolic diseases. In addition to metabolic diseases, like type 2 diabetes, brain insulin resistance is also involved in the progression of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the specific mechanism of sphingolipids in brain insulin resistance has not been systematically summarized. This article reviews the involvement of sphingolipids in brain insulin resistance, highlighting the role and molecular biological mechanism of sphingolipid metabolism in cognitive dysfunctions and neuropathological abnormalities of the brain.

Keywords:  Alzheimer’s disease; Parkinson’s disease; brain insulin resistance; ceramide; sphingolipid metabolism; sphingosine-1-phosphate

DOI:  https://doi.org/10.3389/fendo.2023.1243132
Genes (Basel). 2023 Oct 17. pii: 1949. [Epub ahead of print]14(10):

Identification of Intron Retention in the Slc16a3 Gene Transcript Encoding the Transporter MCT4 in the Brain of Aged and Alzheimer-Disease Model (APPswePS1dE9) Mice.

Ayman El-Seedy, Luc Pellerin, Guylène Page, Veronique Ladeveze.

  The monocarboxylate transporter 4 (MCT4; Slc16a3) is expressed in the central nervous system, notably by astrocytes. It is implicated in lactate release and the regulation of glycolytic flux. Whether its expression varies during normal and/or pathological aging is unclear. As the presence of its mature transcript in the brain of young and old mice was determined, an unexpectedly longer RT-PCR fragment was detected in the mouse frontal cortex and hippocampus at 12 vs. 3 months of age. Cultured astrocytes expressed the expected 516 base pair (bp) fragment but treatment with IL-1β to mimic inflammation as can occur during aging led to the additional expression of a 928 bp fragment like that seen in aged mice. In contrast, cultured pericytes (a component of the blood-brain barrier) only exhibited the 516 bp fragment. Intriguingly, cultured endothelial cells constitutively expressed both fragments. When RT-PCR was performed on brain subregions of an Alzheimer mouse model (APPswePS1dE9), no fragment was detected at 3 months, while only the 928 bp fragment was present at 12 months. Sequencing of MCT4 RT-PCR products revealed the presence of a remaining intron between exon 2 and 3, giving rise to the longer fragment detected by RT-PCR. These results unravel the existence of intron retention for the MCT4 gene in the central nervous system. Such alternative splicing appears to increase with age in the brain and might be prominent in neurodegenerative diseases such as Alzheimer's disease. Hence, further studies in vitro and in vivo of intron 2 retention in the Slc16a3 gene transcript are required for adequate characterization concerning the biological roles of Slc16a3 isoforms in the context of aging and Alzheimer's disease pathology.

Keywords:  Alzheimer; MCT4 transporter; Slc16a3 gene; aging; alternative splicing; astrocyte; intron retention

DOI:  https://doi.org/10.3390/genes14101949
Biochem Biophys Res Commun. 2023 Oct 17. pii: S0006-291X(23)01207-X. [Epub ahead of print]684 149123

N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency.

Vanessa Trindade Bortoluzzi, Rafael Teixeira Ribeiro, Camila Vieira Pinheiro, Ediandra Tissot Castro, Tailine Quevedo Tavares, Guilhian Leipnitz, Jörn Oliver Sass, Roger Frigério Castilho, Alexandre Umpierrez Amaral, Moacir Wajner.

  Aminoacylase 1 (ACY1) deficiency is an inherited metabolic disorder biochemically characterized by high urinary concentrations of aliphatic N-acetylated amino acids and associated with a broad clinical spectrum with predominant neurological signs. Considering that the pathogenesis of ACY1 is practically unknown and the brain is highly dependent on energy production, the in vitro effects of N-acetylglutamate (NAG) and N-acetylmethionine (NAM), major metabolites accumulating in ACY1 deficiency, on the enzyme activities of the citric acid cycle (CAC), of the respiratory chain complexes and glutamate dehydrogenase (GDH), as well as on ATP synthesis were evaluated in brain mitochondrial preparations of developing rats. NAG mildly inhibited mitochondrial isocitrate dehydrogenase 2 (IDH2) activity, moderately inhibited the activities of isocitrate dehydrogenase 3 (IDH3) and complex II-III of the respiratory chain and markedly suppressed the activities of complex IV and GDH. Of note, the NAG-induced inhibitory effect on IDH3 was competitive, whereas that on GDH was mixed. On the other hand, NAM moderately inhibited the activity of respiratory complexes II-III and GDH activities and strongly decreased complex IV activity. Furthermore, NAM was unable to modify any of the CAC enzyme activities, indicating a selective effect of NAG toward IDH mitochondrial isoforms. In contrast, the activities of citrate synthase, α-ketoglutarate dehydrogenase, malate dehydrogenase, and of the respiratory chain complexes I and II were not changed by these N-acetylated amino acids. Finally, NAG and NAM strongly decreased mitochondrial ATP synthesis. Taken together, the data indicate that NAG and NAM impair mitochondrial brain energy homeostasis.

Keywords:  Aminoacylase 1; Brain bioenergetics; Citric acid cycle; N-Acetylglutamate; N-Acetylmethionine; Respiratory chain

DOI:  https://doi.org/10.1016/j.bbrc.2023.149123
Prostaglandins Other Lipid Mediat. 2023 Oct 20. pii: S1098-8823(23)00085-0. [Epub ahead of print] 106788

Plasma oxylipin profiles reflect Parkinson's disease stage.

Dmitry V Chistyakov, Nadezhda V Azbukina, Alexander V Lopachev, Sergei V Goriainov, Alina A Astakhova, Elena V Ptitsyna, Anna S Klimenko, Vsevolod V Poleshuk, Rogneda B Kazanskaya, Tatiana N Fedorova, Marina G Sergeeva.

  Derivatives of polyunsaturated fatty acids (PUFAs), also known as oxylipins, are key participants in regulating inflammation. Neuroinflammation is involved in many neurodegenerative diseases, including Parkinson's disease. The development of ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) facilitated the study of oxylipins on a system level, i.e., the analysis of oxylipin profiles. We analyzed oxylipin profiles in the blood plasma of 36 healthy volunteers (HC) and 73 patients with Parkinson's disease (PD), divided into early (L\M, 29 patients) or advanced (H, 44 patients) stages based on the Hoehn and Yahr scale. Among the 40 oxylipins detected, we observed a decrease in the concentration of arachidonic acid (AA) and AA derivatives, including anandamide (AEA) and Leukotriene E4 (LTE4), and an increase in the concentration of hydroxyeicosatetraenoic acids 19-HETE and 12-HETE (PD vs HC). Correlation analysis of gender, age of PD onset, and disease stages revealed 20 compounds the concentration of which changed depending on disease stage. Comparison of the acquired oxylipin profiles to openly available PD patient brain transcriptome datasets showed that plasma oxylipins do not appear to directly reflect changes in brain metabolism at different disease stages. However, both the L\M and H stages are characterized by their own oxylipin profiles - in patients with the H stage oxylipin synthesis is increased, while in patients with L\M stages oxylipin synthesis decreases compared to HC. This suggests that different therapeutic approaches may be more effective for patients at early versus late stages of PD.

Keywords:  COX; PUFAs; Parkinson disease; UPLC-MS/MS; anandamide; blood profiling; lipidomics; oxylipins; transcriptomics

DOI:  https://doi.org/10.1016/j.prostaglandins.2023.106788
Sci Adv. 2023 Oct 27. 9(43): eadi4462

Disrupting astrocyte-neuron lactate transport prevents cocaine seeking after prolonged withdrawal.

Wenjun Chen, Yan Zhang, Jie Liang, Zhongyu Zhang, Libo Zhang, Enze Huang, Guipeng Zhang, Lin Lu, Ying Han, Jie Shi.

Energy supply, especially the transfer of lactate from astrocytes to neurons, is critical for neuronal plasticity. However, its role in the incubation of cocaine craving remains largely unknown. Using an extended-access self-administration model and in vivo 1H-magnetic resonance spectroscopy, we found that lactate synthesis in the central amygdala (CeA) is required for the intensified cocaine craving after prolonged withdrawal. Furthermore, incubated cocaine seeking was associated with a selective increase in monocarboxylate transporter 2 (MCT2) and MCT4 expression levels. Down-regulation of astrocytic MCT4 or neuronal MCT2 using targeted antisense oligonucleotides or cell type-specific shRNA attenuated cocaine craving and reduced the expression of plasticity-related proteins and excitatory synaptic transmission. Meanwhile, lactate administration rescued MCT4 but not MCT2 disruption-induced behavioral changes due to the inability of lactate to be transported into neurons. Together, our study highlights the critical role of astrocyte-neuron lactate transport in the CeA in the incubation of cocaine craving and suggests a potential therapeutic target for drug addiction.

DOI: https://doi.org/10.1126/sciadv.adi4462
J Lipid Res. 2023 Oct 25. pii: S0022-2275(23)00137-2. [Epub ahead of print] 100464

The atypical sphingolipid SPB 18:1(14Z);O2 is a biomarker for DEGS1 related hypomyelinating leukodystrophy.

Andreas J Hülsmeier, Sandra P Toelle, Peter Bellstedt, Christian Wentzel, Angela Bahr, Konstantinos Kolokotronis, Thorsten Hornemann.

  Sphingolipids (SL) represent a structurally diverse class of lipids that are central to cellular physiology and neuronal development and function. Defects in the sphingolipid metabolism are typically associated with nervous system disorders. The C4-dihydroceramide desaturase (DEGS1) catalyzes the conversion of dihydroceramide to ceramide, the final step in the SL de-novo synthesis. Loss of function mutations in DEGS1 cause a hypomyelinating leukodystrophy, which is associated with increased plasma dihydrosphingolipids (dhSL) and with the formation of an atypical SPB 18:1(14Z);O2 metabolite. Here, we characterize two novel DEGS1 variants of unknown significance (VUS), provide a structural model with a predicted substrate binding site and propose a regulatory link between DEGS1 and fatty acid desaturase 3 (FADS3). Both VUS involve single amino acid substitutions near the C-terminus within conserved regions of the enzyme. Patient 1 (p.R311K variant) shows severe progressive tetraspasticity, intellectual disability, and epilepsy in combination with brain magnetic resonance imaging (MRI) findings, typical for DEGS1-related leukodystrophy. Patient 2 (p.G270E variant) presents with delayed psychomotor development, oculomotor apraxia, and a normal brain MRI. Plasma from the p.R311K carrier showed a significantly elevated dhSL species and the presence of SPB 18:1(14Z);O2, while the plasma SL profile for the p.G270E variant was not altered. This suggests the p.R331K variant is pathogenic, while the p.G270E appears benign. As an increase in dihydroSL species is also seen in other pathological disorders of the SL metabolism, the SPB 18:1(14Z);O2 seems to be a more specific biomarker to discriminate between pathogenic and benign DEGS1 variants.

Keywords:  DEGS1; FADS3; HLD18; SPT; Sphingolipids; biomarker; ceramide; hypomyelinating leukodystrophy; sphingolipidosis

DOI:  https://doi.org/10.1016/j.jlr.2023.100464
Redox Biol. 2023 Oct 16. pii: S2213-2317(23)00327-0. [Epub ahead of print]67 102926

Mitochondrial complex I ROS production and redox signaling in hypoxia.

Chidozie N Okoye, Shon A Koren, Andrew P Wojtovich.

  Mitochondria are a main source of cellular energy. Oxidative phosphorylation (OXPHOS) is the major process of aerobic respiration. Enzyme complexes of the electron transport chain (ETC) pump protons to generate a protonmotive force (Δp) that drives OXPHOS. Complex I is an electron entry point into the ETC. Complex I oxidizes nicotinamide adenine dinucleotide (NADH) and transfers electrons to ubiquinone in a reaction coupled with proton pumping. Complex I also produces reactive oxygen species (ROS) under various conditions. The enzymatic activities of complex I can be regulated by metabolic conditions and serves as a regulatory node of the ETC. Complex I ROS plays diverse roles in cell metabolism ranging from physiologic to pathologic conditions. Progress in our understanding indicates that ROS release from complex I serves important signaling functions. Increasing evidence suggests that complex I ROS is important in signaling a mismatch in energy production and demand. In this article, we review the role of ROS from complex I in sensing acute hypoxia.

Keywords:  Acute hypoxia; Mitochondrial complex I; Oxygen sensing; ROS signaling

DOI:  https://doi.org/10.1016/j.redox.2023.102926
FEBS Open Bio. 2023 Oct 27.

GM1 ganglioside exerts protective effects against glutamate-excitotoxicity via its oligosaccharide in wild-type and amyotrophic lateral sclerosis motor neurons.

Giulia Lunghi, Erika Di Biase, Emma Veronica Carsana, Alexandre Henriques, Noelle Callizot, Laura Mauri, Maria Grazia Ciampa, Luigi Mari, Nicoletta Loberto, Massimo Aureli, Sandro Sonnino, Michael Spedding, Elena Chiricozzi, Maria Fazzari.

  Alterations in glycosphingolipid metabolism have been linked to the pathophysiological mechanisms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Accordingly, administration of GM1, a sialic acid-containing glycosphingolipid, is protective against neuronal damage and supports neuronal homeostasis, with these effects mediated by its bioactive component, the oligosaccharide head (GM1-OS). Here, we add new evidence to the therapeutic efficacy of GM1 in ALS: its administration to WT and SOD1G93A motor neurons affected by glutamate-induced excitotoxicity significantly increased neuronal survival and preserved neurite networks, counteracting intracellular protein accumulation and mitochondria impairment. Importantly, the GM1-OS faithfully replicates GM1 activity, emphasising that even in ALS the protective function of GM1 strictly depends on its pentasaccharide.

Keywords:  Amyotrophic Lateral Sclerosis; GM1 ganglioside; GM1 oligosaccharide; Excitotoxicity; Intracellular aggregates; Mitochondria

DOI:  https://doi.org/10.1002/2211-5463.13727
J Pharmacol Exp Ther. 2023 Oct 24. pii: JPET-AR-2023-001919. [Epub ahead of print]

Pantothenate kinase activation restores brain coenzyme A in a mouse model of pantothenate kinase associated neurodegeneration.

Chitra Subramanian, Matthew W Frank, Rajaa Sukun, Christopher E Henry, Anna Wade, Mallory E Harden, Satish Rao, Rajendra Tangallapally, Mi-Kyung Yun, Stephen W White, Richard E Lee, Uma Sinha, Charles O Rock, Suzanne Jackowski.

  Pantothenate kinase associated neurodegeneration (PKAN) is characterized by a motor disorder with combinations of dystonia, parkinsonism and spasticity, leading to premature death. PKAN is caused by mutations in the PANK2 gene that result in loss or reduction of PANK2 protein function. PANK2 is one of three kinases that initiate and regulate coenzyme A biosynthesis from vitamin B5 and the ability of BBP-671, an allosteric activator of pantothenate kinases, to enter the brain and elevate coenzyme A was investigated. The metabolic stability, protein binding and membrane permeability of BBP-671 all suggest it has the physical properties required to cross the blood brain barrier. BBP-671 was detected in plasma, liver, cerebrospinal fluid and brain following oral administration in rodents demonstrating the ability of BBP-671 to penetrate the brain. The pharmacokinetic and pharmacodynamic properties of orally administered BBP-671 evaluated in cannulated rats showed that CoA concentrations were elevated in blood, liver and brain. BBP-671 elevation of whole blood acetyl-CoA served as a peripheral pharmacodynamic marker and provided a suitable method to assess target engagement. BBP-671 treatment elevated brain coenzyme A concentrations, and improved movement and body weight in a PKAN mouse model. Thus, BBP-671 crosses the blood brain barrier to correct the brain CoA deficiency in a PKAN mouse model resulting in improved locomotion and survival, providing a preclinical foundation for the development of BBP-671 as a potential treatment for PKAN. Significance Statement The blood brain barrier represents a major hurdle for drugs targeting brain metabolism. This work describes the pharmacokinetic/pharmacodynamic properties of BBP-671, a pantothenate kinase activator. BBP-671 crosses the blood brain barrier to correct the neuron-specific CoA deficiency and improve motor function in a mouse model of pantothenate kinase associated neurodegeneration. The central role of CoA and acetyl-CoA in intermediary metabolism suggests that pantothenate kinase activators may be useful in modifying neurological metabolic disorders.

Keywords:  Drug development; blood-brain barrier; neurodegeneration

DOI:  https://doi.org/10.1124/jpet.123.001919
bioRxiv. 2023 Oct 02. pii: 2023.09.29.560159. [Epub ahead of print]

Regulation of astrocyte metabolism by mitochondrial translocator protein 18kDa.

Wyn Firth, Josephine L Robb, Daisy Stewart, Katherine R Pye, Rosemary Bamford, Asami Oguro-Ando, Craig Beall, Kate Lj Ellacott.

The mitochondrial translocator protein 18kDa (TSPO) has been linked to a variety of functions from steroidogenesis to regulation of cellular metabolism and is an attractive therapeutic target for chronic CNS inflammation. Studies in the periphery using Leydig cells and hepatocytes, as well as work in microglia, indicate that the function of TSPO may vary between cells depending on their specialised roles. Astrocytes are critical for providing trophic and metabolic support in the brain as part of their role in maintaining brain homeostasis. Recent work has highlighted that TSPO expression increases in astrocytes under inflamed conditions and may drive astrocyte reactivity. However, relatively little is known about the role TSPO plays in regulating astrocyte metabolism and whether this protein is involved in immunometabolic processes in these cells. Using TSPO-deficient (TSPO -/- ) mouse primary astrocytes in vitro (MPAs) and a human astrocytoma cell line (U373 cells), we performed metabolic flux analyses. We found that loss of TSPO reduced basal astrocyte respiration and increased the bioenergetic response to glucose reintroduction following glucopenia, while increasing fatty acid oxidation (FAO). Lactate production was significantly reduced in TSPO -/- astrocytes. Co-immunoprecipitation studies in U373 cells revealed that TSPO forms a complex with carnitine palmitoyltransferase 1a, which presents a mechanism wherein TSPO may regulate FAO in astrocytes. Compared to TSPO +/+ cells, inflammation induced by 3h lipopolysaccharide (LPS) stimulation of TSPO -/- MPAs revealed attenuated tumour necrosis factor release, which was enhanced in TSPO -/- MPAs at 24h LPS stimulation. Together these data suggest that while TSPO acts as a regulator of metabolic flexibility in astrocytes, loss of TSPO does not appear to modulate the metabolic response of astrocytes to inflammation, at least in response to the stimulus/time course used in this study.

DOI: https://doi.org/10.1101/2023.09.29.560159
Mol Neurobiol. 2023 Oct 23.

The Role of Astrocytic Mitochondria in the Pathogenesis of Brain Ischemia.

Ling-Yan Zhang, Yu-Yan Hu, Xi-Yun Liu, Xiao-Yu Wang, Shi-Chao Li, Jing-Ge Zhang, Xiao-Hui Xian, Wen-Bin Li, Min Zhang.

  The morbidity rate of ischemic stroke is increasing annually with the growing aging population in China. Astrocytes are ubiquitous glial cells in the brain and play a crucial role in supporting neuronal function and metabolism. Increasing evidence shows that the impairment or loss of astrocytes contributes to neuronal dysfunction during cerebral ischemic injury. The mitochondrion is increasingly recognized as a key player in regulating astrocyte function. Changes in astrocytic mitochondrial function appear to be closely linked to the homeostasis imbalance defects in glutamate metabolism, Ca2+ regulation, fatty acid metabolism, reactive oxygen species, inflammation, and copper regulation. Here, we discuss the role of astrocytic mitochondria in the pathogenesis of brain ischemic injury and their potential as a therapeutic target.

Keywords:  Astrocyte; Inflammation; Ischemic stroke; Mitochondria; Mitochondria transfer

DOI:  https://doi.org/10.1007/s12035-023-03714-z
bioRxiv. 2023 Oct 10. pii: 2023.10.10.561760. [Epub ahead of print]

Phosphoglycerate kinase 1 is a central leverage point in Parkinson's disease driven neuronal metabolic deficits.

Alex Kokotos, Aldana Antoniazzi, Santiago Unda, Myung Soo Kokotos, Daehun Park, David Eliezer, Michael Kaplitt, Pietro De Camilli, Timothy Ryan.

Phosphoglycerate kinase 1 (PGK1), the first ATP producing glycolytic enzyme, has emerged as a therapeutic target for Parkinson's Disease (PD), since a potential enhancer of its activity was reported to significantly lower PD risk. We Carried out a suppressor screen of hypometabolic synaptic deficits and demonstrated that PGK1 is the rate limiting enzyme in nerve terminal ATP production. Increasing PGK1 expression in mid-brain dopamine neurons protected against hydroxy-dopamine driven striatal dopamine nerve terminal dysfunction in-vivo and modest changes in PGK1 activity dramatically supressed hypometabolic dysfunction in-vitro. Furthermore, PGK1 is cross-regulated by PARK7(DJ-1), a PD associated molecular chaperone, and synaptic deficits driven by PARK20 (Synaptojanin-1) can be reversed by increasing local synaptic PGK1 activity. These data indicate that nerve terminal bioenergetic deficits may underly a a spectrum of PD susceptibilities and the identification of PGK1 as the limiting enzyme in axonal glycolysis provides a mechanistic underpinning for therapeutic protection.

DOI: https://doi.org/10.1101/2023.10.10.561760
Neuropediatrics. 2023 Oct 23.

Effects of Neonatal Hypoxic-Ischemic Injury on Brain Sterol Synthesis and Metabolism.

Amanda M Dave, Ned A Porter, Zeljka Korade, Eric S Peeples.

BACKGROUND: Neonatal hypoxic-ischemic brain injury (HIBI) results from disruptions to blood supply and oxygen in the perinatal brain. The goal of this study was to measure brain sterol metabolites and plasma oxysterols after injury in a neonatal HIBI mouse model to assess for potential therapeutic targets in the brain biochemistry as well as potential circulating diagnostic biomarkers.METHODS: Postnatal day 9 CD1-IGS mouse pups were randomized to HIBI induced by carotid artery ligation followed by 30 minutes at 8% oxygen or to sham surgery and normoxia. Brain tissue was collected for sterol analysis by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Plasma was collected for oxysterol analysis by LC-MS/MS.
RESULTS: There were minimal changes in brain sterol concentrations in the first 72 hours after HIBI. In severely injured brains, there was a significant increase in desmosterol, 7-DHC, 8-DHC, and cholesterol 24 hours after injury in the ipsilateral tissue. Lanosterol, 24-dehydrolathosterol, and 14-dehydrozymostenol decreased in plasma 24 hours after injury. Severe neonatal HIBI was associated with increased cholesterol and sterol precursors in the cortex at 24 hours after injury.
CONCLUSIONS: Differences in plasma oxysterols were seen at 24 hours but were not present at 30 minutes after injury, suggesting that these sterol intermediates would be of little value as early diagnostic biomarkers.

DOI: https://doi.org/10.1055/s-0043-1776286
J Investig Med. 2023 Oct 21. 10815589231210521

EXPRESS: Cholesterol Deficiency as a Mechanism for Autism: A Valproic Acid Model.

Morgan R Peltier, Jennifer Behbodikhah, Heather A Renna, Saba Ahmed, Ankita Srivastava, Yuko Arita, Lora J Kasselman, Aaron Pinkhasov, Thomas Wisniewski, Joshua De Leon, Allison Bethanne Reiss.

  Dysregulated cholesterol metabolism represents an increasingly recognized feature of Autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Further, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36 and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.

Keywords:  Brain Diseases; Cholesterol

DOI:  https://doi.org/10.1177/10815589231210521
medRxiv. 2023 Oct 04. pii: 2023.10.03.23296500. [Epub ahead of print]

Shared genetic basis informs the roles of polyunsaturated fatty acids in brain disorders.

Huifang Xu, Yitang Sun, Michael Francis, Claire F Cheng, Nitya T R Modulla, J Thomas Brenna, Charleston W K Chiang, Kaixiong Ye.

The neural tissue is rich in polyunsaturated fatty acids (PUFAs), components that are indispensable for the proper functioning of neurons, such as neurotransmission. PUFA nutritional deficiency and imbalance have been linked to a variety of chronic brain disorders, including major depressive disorder (MDD), anxiety, and anorexia. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. Here, we used genome-wide association summary statistics to systematically examine the shared genetic basis between six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917), infer their potential causal relationships, identify colocalized regions, and pinpoint shared genetic variants. Genetic correlation and polygenic overlap analyses revealed a widespread shared genetic basis for 77 trait pairs between six PUFA phenotypes and 16 brain disorders. Two-sample Mendelian randomization analysis indicated potential causal relationships for 16 pairs of PUFAs and brain disorders, including alcohol consumption, bipolar disorder (BIP), and MDD. Colocalization analysis identified 40 shared loci (13 unique) among six PUFAs and ten brain disorders. Twenty-two unique variants were statistically inferred as candidate shared causal variants, including rs1260326 ( GCKR ), rs174564 ( FADS2 ) and rs4818766 ( ADARB1 ). These findings reveal a widespread shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for the potential effects of PUFAs on certain brain disorders, especially MDD, BIP, and alcohol consumption.

DOI: https://doi.org/10.1101/2023.10.03.23296500
Cell Mol Neurobiol. 2023 Oct 24.

BDNF and Lactate as Modulators of Hippocampal CA3 Network Physiology.

Ernesto Griego, Emilio J Galván.

  Growing evidence supports the notion that brain-derived neurotrophic factor (BDNF) and lactate are potent modulators of mammalian brain function. The modulatory actions of those biomolecules influence a wide range of neuronal responses, from the shaping of neuronal excitability to the induction and expression of structural and synaptic plasticity. The biological actions of BDNF and lactate are mediated by their cognate receptors and specific transporters located in the neuronal membrane. Canonical functions of BDNF occur via the tropomyosin-related kinase B receptor (TrkB), whereas lactate acts via monocarboxylate transporters or the hydroxycarboxylic acid receptor 1 (HCAR1). Both receptors are highly expressed in the central nervous system, and some of their physiological actions are particularly well characterized in the hippocampus, a brain structure involved in the neurophysiology of learning and memory. The multifarious neuronal circuitry between the axons of the dentate gyrus granule cells, mossy fibers (MF), and pyramidal neurons of area CA3 is of great interest given its role in specific mnemonic processes and involvement in a growing number of brain disorders. Whereas the modulation exerted by BDNF via TrkB has been extensively studied, the influence of lactate via HCAR1 on the properties of the MF-CA3 circuit is an emerging field. In this review, we discuss the role of both systems in the modulation of brain physiology, with emphasis on the hippocampal CA3 network. We complement this review with original data that suggest cross-modulation is exerted by these two independent neuromodulatory systems.

Keywords:  BNDF; CA3; HCAR1; Hippocampus; Lactate; TrkB

DOI:  https://doi.org/10.1007/s10571-023-01425-6
Glia. 2023 Oct 23.

Drosophila tweety facilitates autophagy to regulate mitochondrial homeostasis and bioenergetics in Glia.

Ho Hang Leung, Christina Mansour, Morgan Rousseau, Anwar Nakhla, Kirill Kiselyov, Kartik Venkatachalam, Ching-On Wong.

  Mitochondria support the energetic demands of the cells. Autophagic turnover of mitochondria serves as a critical pathway for mitochondrial homeostasis. It is unclear how bioenergetics and autophagy are functionally connected. Here, we identify an endolysosomal membrane protein that facilitates autophagy to regulate ATP production in glia. We determined that Drosophila tweety (tty) is highly expressed in glia and localized to endolysosomes. Diminished fusion between autophagosomes and endolysosomes in tty-deficient glia was rescued by expressing the human Tweety Homolog 1 (TTYH1). Loss of tty in glia attenuated mitochondrial turnover, elevated mitochondrial oxidative stress, and impaired locomotor functions. The cellular and organismal defects were partially reversed by antioxidant treatment. We performed live-cell imaging of genetically encoded metabolite sensors to determine the impact of tty and autophagy deficiencies on glial bioenergetics. We found that tty-deficient glia exhibited reduced mitochondrial pyruvate consumption accompanied by a shift toward glycolysis for ATP production. Likewise, genetic inhibition of autophagy in glia resulted in a similar glycolytic shift in bioenergetics. Furthermore, the survival of mutant flies became more sensitive to starvation, underlining the significance of tty in the crosstalk between autophagy and bioenergetics. Together, our findings uncover the role for tty in mitochondrial homeostasis via facilitating autophagy, which determines bioenergetic balance in glia.

Keywords:  Drosophila; autophagy; bioenergetics; endolysosomes; mitochondria; tweety homologs

DOI:  https://doi.org/10.1002/glia.24484
Nat Commun. 2023 Oct 25. 14(1): 6773

Visualization of accessible cholesterol using a GRAM domain-based biosensor.

Dylan Hong Zheng Koh, Tomoki Naito, Minyoung Na, Yee Jie Yeap, Pritisha Rozario, Franklin L Zhong, Kah-Leong Lim, Yasunori Saheki.

Cholesterol is important for membrane integrity and cell signaling, and dysregulation of the distribution of cellular cholesterol is associated with numerous diseases, including neurodegenerative disorders. While regulated transport of a specific pool of cholesterol, known as "accessible cholesterol", contributes to the maintenance of cellular cholesterol distribution and homeostasis, tools to monitor accessible cholesterol in live cells remain limited. Here, we engineer a highly sensitive accessible cholesterol biosensor by taking advantage of the cholesterol-sensing element (the GRAM domain) of an evolutionarily conserved lipid transfer protein, GRAMD1b. Using this cholesterol biosensor, which we call GRAM-W, we successfully visualize in real time the distribution of accessible cholesterol in many different cell types, including human keratinocytes and iPSC-derived neurons, and show differential dependencies on cholesterol biosynthesis and uptake for maintaining levels of accessible cholesterol. Furthermore, we combine GRAM-W with a dimerization-dependent fluorescent protein (ddFP) and establish a strategy for the ultrasensitive detection of accessible plasma membrane cholesterol. These tools will allow us to obtain important insights into the molecular mechanisms by which the distribution of cellular cholesterol is regulated.

DOI: https://doi.org/10.1038/s41467-023-42498-7
FASEB J. 2023 11;37(11): e23261

The ketone body β-hydroxybutyrate shifts microglial metabolism and suppresses amyloid-β oligomer-induced inflammation in human microglia.

Lee-Way Jin, Jacopo Di Lucente, Ulises Ruiz Mendiola, Nopparat Suthprasertporn, Alexey Tomilov, Gino Cortopassi, Kyoungmi Kim, Jon J Ramsey, Izumi Maezawa.

  Fatty acids are metabolized by β-oxidation within the "mitochondrial ketogenic pathway" (MKP) to generate β-hydroxybutyrate (BHB), a ketone body. BHB can be generated by most cells but largely by hepatocytes following exercise, fasting, or ketogenic diet consumption. BHB has been shown to modulate systemic and brain inflammation; however, its direct effects on microglia have been little studied. We investigated the impact of BHB on Aβ oligomer (AβO)-stimulated human iPS-derived microglia (hiMG), a model relevant to the pathogenesis of Alzheimer's disease (AD). HiMG responded to AβO with proinflammatory activation, which was mitigated by BHB at physiological concentrations of 0.1-2 mM. AβO stimulated glycolytic transcripts, suppressed genes in the β-oxidation pathway, and induced over-expression of AD-relevant p46Shc, an endogenous inhibitor of thiolase, actions that are expected to suppress MKP. AβO also triggered mitochondrial Ca2+ increase, mitochondrial reactive oxygen species production, and activation of the mitochondrial permeability transition pore. BHB potently ameliorated all the above mitochondrial changes and rectified the MKP, resulting in reduced inflammasome activation and recovery of the phagocytotic function impaired by AβO. These results indicate that microglia MKP can be induced to modulate microglia immunometabolism, and that BHB can remedy "keto-deficiency" resulting from MKP suppression and shift microglia away from proinflammatory mitochondrial metabolism. These effects of BHB may contribute to the beneficial effects of ketogenic diet intervention in aged mice and in human subjects with mild AD.

Keywords:  Alzheimer's; amyloid; inflammation; ketone; microglia; mitochondria; phagocytosis

DOI:  https://doi.org/10.1096/fj.202301254R
Proc Natl Acad Sci U S A. 2023 Oct 31. 120(44): e2313010120

Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.

Yvette C Wong, Nirupa D Jayaraj, Tayler B Belton, George C Shum, Hannah E Ball, Dongjun Ren, Abigail L D Tadenev, Dimitri Krainc, Robert W Burgess, Daniela M Menichella.

  Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria-lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot-Marie-Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria-lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot-Marie-Tooth type 2B mutant Rab7 led to prolonged mitochondria-lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis-mediated contact site untethering. We further generated a Charcot-Marie-Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria-lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria-lysosome contact sites in the pathogenesis of peripheral neuropathy.

Keywords:  Charcot–Marie–Tooth disease; inter-organelle contact site; lysosome; mitochondria; peripheral neuropathy

DOI:  https://doi.org/10.1073/pnas.2313010120
J Lipid Res. 2023 Oct 21. pii: S0022-2275(23)00136-0. [Epub ahead of print] 100463

Sialidase NEU3 action on GM1 ganglioside is neuroprotective in GM1 Gangliosidosis.

Maria L Allende, Y Terry Lee, Colleen Byrnes, Cuiling Li, Galina Tumetova, Jenna Y Bakir, Elena-Raluca Nicoli, Virginia K James, Jennifer S Brodbelt, Cynthia J Tifft, Richard L Proia.

  GM1 gangliosidosis is a neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes lysosomal β-galactosidase. The enzyme deficiency blocks GM1 ganglioside catabolism, leading to accumulation of GM1 ganglioside and asialo-GM1 ganglioside (GA1 glycolipid) in brain. This disease can present in varying degrees of severity, with the level of residual β-galactosidase activity primarily determining the clinical course. Glb1 null mouse models, which completely lack β-galactosidase expression, exhibit a less severe form of the disease than expected from the comparable deficiency in humans, suggesting a potential species difference in the GM1 ganglioside degradation pathway. We hypothesized this difference may involve the sialidase NEU3, which acts on GM1 ganglioside to produce GA1 glycolipid. To test this hypothesis, we generated Glb1/Neu3 double knockout (DKO) mice. These mice had a significantly shorter lifespan, increased neurodegeneration, and more severe ataxia than Glb1 KO mice. Glb1/Neu3 DKO mouse brains exhibited an increased GM1 ganglioside to GA1 glycolipid ratio compared with Glb1 KO mice, indicating that NEU3 mediated GM1 ganglioside to GA1 glycolipid conversion in Glb1 KO mice. The expression of genes associated with neuroinflammation and glial responses were enhanced in Glb1/Neu3 DKO mice compared with Glb1 KO mice. Mouse NEU3 more efficiently converted GM1 ganglioside to GA1 glycolipid than human NEU3 did. Our findings highlight NEU3's role in ameliorating the consequences of Glb1 deletion in mice, provide insights into NEU3's differential effects between mice and humans in GM1 gangliosidosis, and offer a potential therapeutic approach for reducing toxic GM1 ganglioside accumulation in GM1 gangliosidosis patients.

Keywords:  Brain Lipids; Glycolipids; Inflammation Storage Diseases; Sphingolipids

DOI:  https://doi.org/10.1016/j.jlr.2023.100463
Biochem Pharmacol. 2023 Oct 21. pii: S0006-2952(23)00460-4. [Epub ahead of print]218 115869

A strategic tool to improve the study of molecular determinants of Alzheimer's disease: The role of glyceraldehyde.

Silvia Piccirillo, Alessandra Preziuso, Giorgia Cerqueni, Tiziano Serfilippi, Valentina Terenzi, Antonio Vinciguerra, Salvatore Amoroso, Vincenzo Lariccia, Simona Magi.

  Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by progressive neurodegeneration leading to severe cognitive, memory, and behavioral impairments. The onset of AD involves a complex interplay among various factors, including age, genetics, chronic inflammation, and impaired energy metabolism. Despite significant efforts, there are currently no effective therapies capable of modifying the course of AD, likely owing to an excessive focus on the amyloid hypothesis and a limited consideration of other intracellular pathways. In the present review, we emphasize the emerging concept of AD as a metabolic disease, where alterations in energy metabolism play a critical role in its development and progression. Notably, glucose metabolism impairment is associated with mitochondrial dysfunction, oxidative stress, Ca2+ dyshomeostasis, and protein misfolding, forming interconnected processes that perpetuate a detrimental self-feeding loop sustaining AD progression. Advanced glycation end products (AGEs), neurotoxic compounds that accumulate in AD, are considered an important consequence of glucose metabolism disruption, and glyceraldehyde (GA), a glycolytic intermediate, is a key contributor to AGEs formation in both neurons and astrocytes. Exploring the impact of GA-induced glucose metabolism impairment opens up exciting possibilities for creating an easy-to-handle in vitro model that recapitulates the early stage of the disease. This model holds great potential for advancing the development of novel therapeutics targeting various intracellular pathways implicated in AD pathogenesis. In conclusion, looking beyond the conventional amyloid hypothesis could lead researchers to discover promising targets for intervention, offering the possibility of addressing the existing medical gaps in AD treatment.

Keywords:  Advanced glycation end products (AGEs); Alzheimer's disease; Glucose metabolism impairment; In vitro model

DOI:  https://doi.org/10.1016/j.bcp.2023.115869
Crit Rev Food Sci Nutr. 2023 Oct 27. 1-22

Gut microbiota-derived short chain fatty acids act as mediators of the gut-brain axis targeting age-related neurodegenerative disorders: a narrative review.

Bingbing Guo, Jingyi Zhang, Weihao Zhang, Feng Chen, Bin Liu.

  Neurodegenerative diseases associated with aging are often accompanied by cognitive decline and gut microbiota disorder. But the impact of gut microbiota on these cognitive disturbances remains incompletely understood. Short chain fatty acids (SCFAs) are major metabolites produced by gut microbiota during the digestion of dietary fiber, serving as an energy source for gut epithelial cells and/or circulating to other organs, such as the liver and brain, through the bloodstream. SCFAs have been shown to cross the blood-brain barrier and played crucial roles in brain metabolism, with potential implications in mediating Alzheimer's disease (AD) and Parkinson's disease (PD). However, the underlying mechanisms that SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, the dietary sources which determine these SCFAs production was not thoroughly evaluated yet. This comprehensive review explores the production of SCFAs by gut microbiota, their transportation through the gut-brain axis, and the potential mechanisms by which they influence age-related neurodegenerative disorders. Also, the review discusses the importance of dietary fiber sources and the challenges associated with harnessing dietary-derived SCFAs as promoters of neurological health in elderly individuals. Overall, this study suggests that gut microbiota-derived SCFAs and/or dietary fibers hold promise as potential targets and strategies for addressing age-related neurodegenerative disorders.

Keywords:  Dietary fiber; gut microbiota; gut–brain-axis; short chain fatty acids

DOI:  https://doi.org/10.1080/10408398.2023.2272769
Int J Neonatal Screen. 2023 Oct 06. pii: 53. [Epub ahead of print]9(4):

Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency: Family Impact and Perspectives.

Sarah Crawford, Elizabeth Sablon, Nadia Ali, Ami R Rosen, Patricia L Hall, Juanita Neira Fresneda.

  Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD) is a fatty acid oxidation disorder characterized by the decreased ability of the enzyme very-long-chain acyl-CoA dehydrogenase to break down fatty acids with 14 to 20-long carbon chains. The resulting clinical manifestations are variable in severity and include hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. Treatment can consist of limiting the dietary intake of long-chain fatty acids, the prevention of fasting, and the supplementation of medium-chain fats. This study, conducted in the context of a 5-year long-term follow-up on VLCADD, evaluates how the diagnosis of this fatty acid disorder impacts the family, specifically as it relates to the medical diet and barriers to care. Caregivers (n = 10) of individuals with VLCADD responded to a survey about how VLCADD potentially impacts their family. The review included the clinical outcomes of the patients (n = 11), covering instances of rhabdomyolysis, cardiomyopathy, and hospitalizations related to VLCADD. Families affected by VLCADD experience barriers to care, including difficulties with finances, ability to work, and access to nutrition.

Keywords:  VLCADD; barriers; cardiomyopathy; caregiver; medical diet; metabolism; rhabdomyolysis

DOI:  https://doi.org/10.3390/ijns9040053
Pharmaceuticals (Basel). 2023 Sep 26. pii: 1359. [Epub ahead of print]16(10):

Patient-Derived Cellular Models for Polytarget Precision Medicine in Pantothenate Kinase-Associated Neurodegeneration.

Mónica Álvarez-Córdoba, Marta Talaverón-Rey, Suleva Povea-Cabello, Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Diana Reche-López, Manuel Munuera-Cabeza, Alejandra Suárez-Carrillo, Ana Romero-González, Jose Manuel Romero-Domínguez, Alejandra López-Cabrera, José Ángel Armengol, José Antonio Sánchez-Alcázar.

  The term neurodegeneration with brain iron accumulation (NBIA) brings together a broad set of progressive and disabling neurological genetic disorders in which iron is deposited preferentially in certain areas of the brain. Among NBIA disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by pathologic variants in the PANK2 gene codifying the enzyme pantothenate kinase 2 (PANK2). To date, there are no effective treatments to stop the progression of these diseases. This review discusses the utility of patient-derived cell models as a valuable tool for the identification of pharmacological or natural compounds for implementing polytarget precision medicine in PKAN. Recently, several studies have described that PKAN patient-derived fibroblasts present the main pathological features associated with the disease including intracellular iron overload. Interestingly, treatment of mutant cell cultures with various supplements such as pantothenate, pantethine, vitamin E, omega 3, α-lipoic acid L-carnitine or thiamine, improved all pathophysiological alterations in PKAN fibroblasts with residual expression of the PANK2 enzyme. The information provided by pharmacological screenings in patient-derived cellular models can help optimize therapeutic strategies in individual PKAN patients.

Keywords:  L-carnitine; fibroblasts; induced neurons; neurodegeneration with brain iron accumulation (NBIA); omega 3; pantethine; pantothenate; pantothenate kinase 2 (PANK2); pantothenate kinase-associated neurodegeneration (PKAN); precision medicine; thiamine; vitamin E; α-lipoic acid

DOI:  https://doi.org/10.3390/ph16101359
Sci Rep. 2023 10 24. 13(1): 18129

Disrupted brain mitochondrial morphology after in vivo hydrogen sulfide exposure.

Wilson K Rumbeiha, Dong-Suk Kim, Angela Min, Maya Nair, Cecilia Giulivi.

Changes in mitochondrial dynamics are often associated with dietary patterns, medical treatments, xenobiotics, and diseases. Toxic exposures to hydrogen sulfide (H2S) harm mitochondria by inhibiting Complex IV and via other mechanisms. However, changes in mitochondrial dynamics, including morphology following acute exposure to H2S, are not yet fully understood. This study followed mitochondrial morphology changes over time after a single acute LCt50 dose of H2S by examining electron microscopy thalami images of surviving mice. Our findings revealed that within the initial 48 h after H2S exposure, mitochondrial morphology was impaired by H2S, supported by the disruption and scarcity of the cristae, which are required to enhance the surface area for ATP production. At the 72-h mark point, a spectrum of morphological cellular changes was observed, and the disordered mitochondrial network, accompanied by the probable disruption of mitophagy, was tied to changes in mitochondrial shape. In summary, this study sheds light on how acute exposure to high levels of H2S triggers alterations in mitochondrial shape and structure as early as 24 h that become more evident at 72 h post-exposure. These findings underscore the impact of H2S on mitochondrial function and overall cellular health.

DOI: https://doi.org/10.1038/s41598-023-44807-y
Endocr Metab Immune Disord Drug Targets. 2023 Oct 20.

Insights on the Correlation between Mitochondrial Dysfunction and the Progression of Parkinson's Disease.

Prashant Chauhan, Pratibha Pandey, Fahad Khan, Ramish Maqsood.

  The aetiology of a progressive neuronal Parkinson's disease has been discussed in several studies. However, due to the multiple risk factors involved in its development, such as environmental toxicity, parental inheritance, misfolding of protein, ageing, generation of reactive oxygen species, degradation of dopaminergic neurons, formation of neurotoxins, mitochondria dysfunction, and genetic mutations, its mechanism of involvement is still discernible. Therefore, this study aimed to review the processes or systems that are crucially implicated in the conversion of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) into its lethal form, which directly blockades the performance of mitochondria, leading to the formation of oxidative stress in the dopaminergic neurons of substantia nigra pars compacta (SNpc) and resulting in the progression of an incurable Parkinson's disease. This review also comprises an overview of the mutated genes that are frequently associated with mitochondrial dysfunction and the progression of Parkinson's disease. Altogether, this review would help future researchers to develop an efficient therapeutic approach for the management of Parkinson's disease via identifying potent prognostic and diagnostic biomarkers.

Keywords:  Mitochondrial dysfunction; Parkinson; biomarker; disease; neurodegenerative

DOI:  https://doi.org/10.2174/0118715303249690231006114308
Biomolecules. 2023 Sep 26. pii: 1449. [Epub ahead of print]13(10):

Neonatal Maternal Separation Induces Sexual Dimorphism in Brain Development: The Influence on Amino Acid Levels and Cognitive Disorders.

Jolanta H Kotlinska, Pawel Grochecki, Agnieszka Michalak, Anna Pankowska, Katarzyna Kochalska, Piotr Suder, Joanna Ner-Kluza, Dariusz Matosiuk, Marta Marszalek-Grabska.

  Repeated maternal separation (MS) is a useful experimental model in rodents for studying the long-term influence of early-life stress on brain neurophysiology. In our work, we assessed the effect of repeated MS (postnatal day (PND)1-21, 180 min/day) on the postnatal development of rat brain regions involved in memory using proton magnetic resonance spectroscopy (1HMRS) for tissue volume and the level of amino acids such as glutamate, aspartate, glutamine, glycine and gamma-aminobutyric acid (GABA) in the hippocampus. We assessed whether these effects are sex dependent. We also use novel object recognition (NOR) task to examine the effect of MS on memory and the effect of ethanol on it. Finally, we attempted to ameliorate postnatal stress-induced memory deficits by using VU-29, a positive allosteric modulator (PAM) of the metabotropic glutamate type 5 (mGlu5) receptor. In males, we noted deficits in the levels of glutamate, glycine and glutamine and increases in GABA in the hippocampus. In addition, the values of perirhinal cortex, prefrontal cortex and insular cortex and CA3 were decreased in these animals. MS females, in contrast, demonstrated significant increase in glutamate levels and decrease in GABA levels in the hippocampus. Here, the CA1 values alone were increased. VU-29 administration ameliorated these cognitive deficits. Thus, MS stress disturbs amino acids levels mainly in the hippocampus of adult male rats, and enhancement of glutamate neurotransmission reversed recognition memory deficits in these animals.

Keywords:  amino acids; hippocampus; mGlu5; maternal separation; rats; recognition memory; sex

DOI:  https://doi.org/10.3390/biom13101449
J Neurosci. 2023 Oct 26. pii: JN-RM-1113-23. [Epub ahead of print]

Loss of Depalmitoylation Disrupts Homeostatic Plasticity of AMPARs in a Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis.

Kevin P Koster, Eden Flores-Barrera, Emilce Artur de la Villarmois, Adriana Caballero, Kuei Y Tseng, Akira Yoshii.

Protein palmitoylation is the only reversible post-translational lipid modification. Palmitoylation is held in delicate balance by depalmitoylation to precisely regulate protein turnover. While over 20 palmitoylation enzymes are known, depalmitoylation is carried out by fewer enzymes. Of particular interest is the lack of the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1) that causes the devastating pediatric neurodegenerative condition infantile neuronal ceroid lipofuscinosis (CLN1). While most of the research on Ppt1 function has centered on its role in the lysosome, recent findings demonstrated that many Ppt1 substrates are synaptic proteins, including the AMPAR subunit GluA1. Still, the impact of Ppt1-mediated depalmitoylation on synaptic transmission and plasticity remains elusive. Thus, the goal of the present study was to utilize the Ppt1-/- mouse model (both sexes) to determine if Ppt1 regulates AMPAR-mediated synaptic transmission and plasticity, which are crucial for the maintenance of homeostatic adaptations in cortical circuits. Here we found that basal excitatory transmission in the Ppt1-/- visual cortex is developmentally regulated and that chemogenetic silencing of the Ppt1-/- visual cortex excessively enhanced the synaptic expression of GluA1. Furthermore, triggering homeostatic plasticity in Ppt1-/- primary neurons caused an exaggerated incorporation of GluA1-containing, calcium-permeable AMPARs, which correlated with increased GluA1 palmitoylation. Finally, Ca2+ imaging in awake Ppt1-/- mice showed visual cortical neurons favor a state of synchronous firing. Collectively, our results elucidate a crucial role for Ppt1 in AMPAR trafficking and show that impeded proteostasis of palmitoylated synaptic proteins drives maladaptive homeostatic plasticity and abnormal recruitment of cortical activity in CLN1.Significance StatementNeuronal communication is orchestrated by the movement of receptors to and from the synaptic membrane. Protein palmitoylation is the only reversible post-translational lipid modification, a process that must be balanced precisely by depalmitoylation. The significance of depalmitoylation is evidenced by the discovery that mutation of the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (Ppt1) causes severe pediatric neurodegeneration. In this study, we found that the equilibrium provided by Ppt1-mediated depalmitoylation is critical for AMPAR-mediated plasticity and associated homeostatic adaptations of synaptic transmission in cortical circuits. This finding complements the recent explosion of palmitoylation research by emphasizing the necessity of balanced depalmitoylation.

DOI: https://doi.org/10.1523/JNEUROSCI.1113-23.2023
Int J Biol Macromol. 2023 Oct 20. pii: S0141-8130(23)04408-2. [Epub ahead of print] 127511

Mitochondrial glutamate transporter SLC25A22 uni-directionally export glutamate for metabolic rewiring in radioresistant glioblastoma.

Eunguk Shin, Byeongsoo Kim, Hyunkoo Kang, Haksoo Lee, Junhyung Park, JiHoon Kang, Eunho Park, Sunmi Jo, Hae Yu Kim, Jung Sub Lee, Jae-Myung Lee, HyeSook Youn, BuHyun Youn.

  Glioblastoma Multiforme (GBM) is a malignant primary brain tumor. Radiotherapy, one of the standard treatments for GBM patients, could induce GBM radioresistance via rewiring cellular metabolism. However, the precise mechanism attributing to GBM radioresistance or targeting strategies to overcome GBM radioresistance are lacking. Here, we demonstrate that SLC25A22, a mitochondrial bi-directional glutamate transporter, is upregulated and showed uni-directionality from mitochondria to cytosol in radioresistant GBM cells, resulting in accumulating cytosolic glutamate. However, mitochondrial glutaminolysis-mediated TCA cycle metabolites and OCR are maintained constantly. The accumulated cytosolic glutamate enhances the glutathione (GSH) production and proline synthesis in radioresistant GBM cells. Increased GSH protects cells against ionizing radiation (IR)-induced reactive oxygen species (ROS) whereas increased proline, a rate-limiting substrate for collagen biosynthesis, induces extracellular matrix (ECM) remodeling, leading to GBM invasive phenotypes. Finally, we discover that genetic inhibition of SLC25A22 using miR-184 mimic decreases GBM radioresistance and aggressiveness both in vitro and in vivo. Collectively, our study suggests that SLC25A22 upregulation confers GBM radioresistance by rewiring glutamate metabolism, and SLC25A22 could be a significant therapeutic target to overcome GBM radioresistance.

Keywords:  Glioblastoma; Radioresistance; SLC25A22

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127511
bioRxiv. 2023 Oct 02. pii: 2023.10.02.560519. [Epub ahead of print]

Lysosomal proteomics reveals mechanisms of neuronal apoE4-associated lysosomal dysfunction.

Einar K Krogsaeter, Justin McKetney, Angelica Marquez, Zeynep Cakir, Erica Stevenson, Gwendolyn M Jang, Antara Rao, Anton Zhou, Yadong Huang, Nevan J Krogan, Danielle L Swaney.

ApoE4 is the primary risk factor for Alzheimer's Disease. While apoE is primarily expressed by astrocytes, AD pathology including endosomal abnormalities and mitochondrial dysfunction first occurs in neurons. Lysosomes are poised at the convergence point between these features. We find that apoE4-expressing cells exhibit lysosomal alkalinization, reduced lysosomal proteolysis, and impaired mitophagy. To identify driving factors for this lysosomal dysfunction, we performed quantitative lysosomal proteome profiling. This revealed that apoE4 expression results in lysosomal depletion of Lgals3bp and accumulation of Tmed5 in both Neuro-2a cells and postmitotic human neurons. Modulating the expression of both proteins affected lysosomal function, with Tmed5 knockdown rescuing lysosomal alkalinization in apoE4 cells, and Lgals3bp knockdown causing lysosomal alkalinization and reduced lysosomal density in apoE3 cells. Taken together, our work reveals that apoE4 exerts gain-of-toxicity by alkalinizing the lysosomal lumen, pinpointing lysosomal Tmed5 accumulation and Lgals3bp depletion as apoE4-associated drivers for this phenotype.

DOI: https://doi.org/10.1101/2023.10.02.560519
Biomolecules. 2023 Oct 23. pii: 1562. [Epub ahead of print]13(10):

Untargeted Lipidomic Approach for Studying Different Nervous System Tissues of the Murine Model of Krabbe Disease.

Husam B R Alabed, Ambra Del Grosso, Valeria Bellani, Lorena Urbanelli, Sara Carpi, Miriam De Sarlo, Lorenzo Bertocci, Laura Colagiorgio, Sandra Buratta, Luca Scaccini, Dorotea Frongia Mancini, Ilaria Tonazzini, Marco Cecchini, Carla Emiliani, Roberto Maria Pellegrino.

  Krabbe disease is a rare neurodegenerative disease with an autosomal recessive character caused by a mutation in the GALC gene. The mutation leads to an accumulation of psychosine and a subsequent degeneration of oligodendrocytes and Schwann cells. Psychosine is the main biomarker of the disease. The Twitcher mouse is the most commonly used animal model to study Krabbe disease. Although there are many references to this model in the literature, the lipidomic study of nervous system tissues in the Twitcher model has received little attention. This study focuses on the comparison of the lipid profiles of four nervous system tissues (brain, cerebellum, spinal cord, and sciatic nerve) in the Twitcher mouse compared to the wild-type mouse. Altogether, approximately 230 molecular species belonging to 19 lipid classes were annotated and quantified. A comparison at the levels of class, molecular species, and lipid building blocks showed significant differences between the two groups, particularly in the sciatic nerve. The in-depth study of the lipid phenotype made it possible to hypothesize the genes and enzymes involved in the changes. The integration of metabolic data with genetic data may be useful from a systems biology perspective to gain a better understanding of the molecular basis of the disease.

Keywords:  Krabbe disease; LC/MS; Twitcher mouse; lipidomics; psychosine; untargeted mass spectrometry

DOI:  https://doi.org/10.3390/biom13101562