bims-medebr 2023-04-09 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒04‒09
twenty papers selected by
Regina F. Fernández
Johns Hopkins University

Oligodendrocyte-derived transcellular signaling regulates axonal energy metabolism.
24-hydroxycholesterol replacement rate measured in blood is a non-invasive biomarker of brain demyelination and remyelination in cuprizone-treated mice.
The Niemann-Pick type diseases - A synopsis of inborn errors in sphingolipid and cholesterol metabolism.
Promotion of astrocyte-neuron glutamate-glutamine shuttle by SCFA contributes to the alleviation of Alzheimer's disease.
Neurons require glucose uptake and glycolysis in vivo.
Sphingomyelin 16:0 is a therapeutic target for neuronal death in acid sphingomyelinase deficiency.
Glial Glutamate Transporter-Mediated Plasticity: System xc-/xCT/SLC7A11 and EAAT1/2 in Brain Diseases.
Medium Chain Acyl-CoA Dehydrogenase Deficiency: 3 years of Newborn Screening.
Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense.
Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization.
Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer's disease brain.
Neonatal hyperbilirubinemia differentially alters the neurochemical profiles of the developing cerebellum and hippocampus in a preterm Gunn rat model.
Analysis of fatty acid composition and sensitivity to dietary n-3 PUFA intervention of mouse n-3 PUFA-enriched tissues/organs.
Neuroprotective actions of a fatty acid nitroalkene in Parkinson's disease.
Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease.
Severe neurometabolic phenotype in npc1 -/- zebrafish with a C-terminal mutation.
Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system.
Targeting mitochondrial energetics reverses panobinostat- and marizomib-induced resistance in pediatric and adult high-grade gliomas.
The relationship of omega-3 fatty acids with dementia and cognitive decline: evidence from perspective cohort studies of supplementation, dietary intake, and blood markers.
Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.

Curr Opin Neurobiol. 2023 Apr 05. pii: S0959-4388(23)00047-8. [Epub ahead of print]80 102722

Oligodendrocyte-derived transcellular signaling regulates axonal energy metabolism.

Sunan Li, Zu-Hang Sheng.

  The unique morphology and functionality of central nervous system (CNS) neurons necessitate specialized mechanisms to maintain energy metabolism throughout long axons and extensive terminals. Oligodendrocytes (OLs) enwrap CNS axons with myelin sheaths in a multilamellar fashion. Apart from their well-established function in action potential propagation, OLs also provide intercellular metabolic support to axons by transferring energy metabolites and delivering exosomes consisting of proteins, lipids, and RNAs. OL-derived metabolic support is crucial for the maintenance of axonal integrity; its dysfunction has emerged as an important player in neurological disorders that are associated with axonal energy deficits and degeneration. In this review, we discuss recent advances in how these transcellular signaling pathways maintain axonal energy metabolism in health and neurological disorders.

Keywords:  ATP supply; Axonal bioenergetics; Energy metabolism; Exosome; Glycolysis; Metabolite shuttling; Mitochondria; Myelin; Neurodegeneration; Oligodendrocyte

DOI:  https://doi.org/10.1016/j.conb.2023.102722
Exp Neurol. 2023 Mar 30. pii: S0014-4886(23)00079-1. [Epub ahead of print] 114395

24-hydroxycholesterol replacement rate measured in blood is a non-invasive biomarker of brain demyelination and remyelination in cuprizone-treated mice.

Mahalakshmi Shankaran, Hussein Mohammed, Ellen Tsang, Po-Yin Anne Wong, Joan Protasio, Elizabeth J Murphy, Frederic Bernard, Rui Chang, Tammy Dellovade, Scott Turner, Marc K Hellerstein.

  In mice, dietary cuprizone causes brain demyelination with subsequent spontaneous remyelination upon return to normal chow. Heavy water (2H2O) labeling with mass spectrometric analysis can be used to measure brain de novo synthesis of several myelin components including cholesterol, phospholipids, galactocereboside (GalC) and myelin-associated proteins. 24-hydroxycholesterol (24-OHC), the major metabolite of brain cholesterol, is detected in blood and is believed to be specifically derived from CNS cholesterol metabolism. We assessed changes in syntheses of myelin components in brain and of blood sterols during cuprizone-induced experimental demyelination and remyelination, with and without thyroid hormone (T3) treatment. Mice were fed cuprizone for 4 weeks, then returned to control diet and treated with either placebo or T3 (0.005 mg/day). 2H2O was administered for the last 14 days of cuprizone diet, and for either 6, 12 or 19 days of treatment during recovery from cuprizone, after which blood and corpus callosum (CC) samples were collected (n = 5/time point/treatment). 2H incorporation into cholesterol and 24-OHC in blood and CC, and incorporation into phospholipid (PL)-palmitate, GalC, myelin basic protein (MBP) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) in CC were measured. Cuprizone significantly (p < 0.05) decreased syntheses of cholesterol, 24-OHC, GalC, MBP, CNPase and PL-palmitate in the CC and these effects were all reversed during recovery. T3 treatment significantly (p < 0.05) increased syntheses of cholesterol, 24-OHC and palmitate compared to placebo. 24-OHC and cholesterol turnover rates in brain and blood were nearly identical and 24-OHC rates in blood paralleled rates in CC, indicating that blood 24-OHC derives primarily from the brain and reflects oligodendrocyte function. In summary, changes in synthesis of several lipid and protein components in brain during cuprizone-induced demyelination and remyelination are measurable through stable isotope labeling. Blood 24-OHC turnover rates closely reflect flux rates of brain cholesterol in response to cuprizone and T3, which alter oligodendrocyte function. Labeling of blood 24-OHC has potential as a non-invasive marker of brain de novo cholesterol synthesis and breakdown rates in demyelinating conditions.

Keywords:  24-hydroxycholesterol; Biomarker; Brain; Cuprizone; Lipids; Myelin; Remyelination; Turnover

DOI:  https://doi.org/10.1016/j.expneurol.2023.114395
Prog Lipid Res. 2023 Mar 30. pii: S0163-7827(23)00015-2. [Epub ahead of print] 101225

The Niemann-Pick type diseases - A synopsis of inborn errors in sphingolipid and cholesterol metabolism.

Frank W Pfrieger.

  Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.

Keywords:  Ceramide; Cholesterol; Lipidosis; Lysosomal storage disorder; Lysosome; Neurodegeneration; Neurologic; Psychiatric; Sphingolipids; Sterol

DOI:  https://doi.org/10.1016/j.plipres.2023.101225
Redox Biol. 2023 Mar 27. pii: S2213-2317(23)00091-5. [Epub ahead of print]62 102690

Promotion of astrocyte-neuron glutamate-glutamine shuttle by SCFA contributes to the alleviation of Alzheimer's disease.

Yan Sun, Huaiwu Zhang, Xuan Zhang, Wenzhao Wang, Yong Chen, Zhiyou Cai, Qihui Wang, Jun Wang, Yi Shi.

  The brain is particularly susceptible to oxidative damage which is a key feature of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease. The shuttling of glutathione (GSH) precursors from astrocytes to neurons has been shown to be instrumental for the neuroprotective activity. Here, we revealed that short chain fatty acids (SCFA), which have been related to AD and PD, could promote glutamate-glutamine shuttle to potentially resist oxidative damage in neurons at cellular level. Furthermore, we performed nine-month-long dietary SCFA supplementations in APPswe/PS1dE9 (APP/PS1) mice, and showed that it reshaped the homeostasis of microbiota and alleviated the cognitive impairment by reducing Aβ deposition and tau hyperphosphorylation. Single-cell RNA sequencing analysis of the hippocampus revealed SCFA can enhance astrocyte-neuron communication including glutamate-glutamine shuttle, mainly by acting on astrocyte in vivo. Collectively, our findings indicate that long-term dietary SCFA supplementations at early aging stage can regulate the neuroenergetics to alleviate AD, providing a promising direction for the development of new AD drug.

Keywords:  Alzheimer's disease; Astrocyte; Glutamate-glutamine shuttle; Neuroenergetics; ROS; Short chain fatty acids

DOI:  https://doi.org/10.1016/j.redox.2023.102690
Cell Rep. 2023 Apr 06. pii: S2211-1247(23)00346-7. [Epub ahead of print]42(4): 112335

Neurons require glucose uptake and glycolysis in vivo.

Huihui Li, Caroline Guglielmetti, Yoshitaka J Sei, Misha Zilberter, Lydia M Le Page, Lauren Shields, Joyce Yang, Kevin Nguyen, Brice Tiret, Xiao Gao, Neal Bennett, Iris Lo, Talya L Dayton, Martin Kampmann, Yadong Huang, Jeffrey C Rathmell, Matthew Vander Heiden, Myriam M Chaumeil, Ken Nakamura.

  Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.

Keywords:  CP: Neuroscience; bioenergetics; brain energy; galactose metabolism; glucose transporter; glycolysis; hyperpolarized magnetic resonance spectroscopic imaging; metabolomics; neuronal glucose metabolism; pyruvate kinase

DOI:  https://doi.org/10.1016/j.celrep.2023.112335
Cell Death Dis. 2023 Apr 06. 14(4): 248

Sphingomyelin 16:0 is a therapeutic target for neuronal death in acid sphingomyelinase deficiency.

Ángel Gaudioso, Xuntian Jiang, Josefina Casas, Edward H Schuchman, María Dolores Ledesma.

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the SMPD1 gene encoding for the acid sphingomyelinase (ASM). While intravenous infusion of recombinant ASM is an effective treatment for the peripheral disease, the neurological complications of ASMD remain unaddressed. It has been shown that aberrantly high level of total brain sphingomyelin (SM) is a key pathological event leading to neurodegeneration. Using mice lacking ASM (ASMko), which mimic the disease, we here demonstrate that among the SM species, SM16:0 shows the highest accumulation and toxicity in ASMko neurons. By targeting lysosomes, SM16:0 causes permeabilization and exocytosis of these organelles and induces oxidative stress and cell death. We also show that genetic silencing of Ceramide Synthase 5, which is involved in SM16:0 synthesis and overexpressed in the ASMko brain, prevents disease phenotypes in ASMko cultured neurons and mice. The levels of SM16:0 in plasma also show a strong correlation with those in brain that is higher than in liver, even at early stages of the disease. These results identify SM16:0 both as a novel therapeutic target and potential biomarker of brain pathology in ASMD.

DOI: https://doi.org/10.1038/s41419-023-05784-2
Front Biosci (Landmark Ed). 2023 03 20. 28(3): 57

Glial Glutamate Transporter-Mediated Plasticity: System xc-/xCT/SLC7A11 and EAAT1/2 in Brain Diseases.

Marc Dahlmanns, Jana Katharina Dahlmanns, Nicolai Savaskan, Hans-Herbert Steiner, Eduard Yakubov.

  Glial cells play an essential role in the complex function of the nervous system. In particular, astrocytes provide nutritive support for neuronal cells and are involved in regulating synaptic transmission. Oligodendrocytes ensheath axons and support information transfer over long distances. Microglial cells constitute part of the innate immune system in the brain. Glial cells are equipped with the glutamate-cystine-exchanger xCT (SLC7A11), the catalytic subunit of system xc-, and the excitatory amino acid transporter 1 (EAAT1, GLAST) and EAAT2 (GLT-1). Thereby, glial cells maintain balanced extracellular glutamate levels that enable synaptic transmission and prevent excitotoxic states. Expression levels of these transporters, however, are not fixed. Instead, expression of glial glutamate transporters are highly regulated in reaction to the external situations. Interestingly, such regulation and homeostasis is lost in diseases such as glioma, (tumor-associated) epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or multiple sclerosis. Upregulation of system xc- (xCT or SLC7A11) increases glutamate export from the cell, while a downregulation of EAATs decreases intracellular glutamate import. Occurring simultaneously, these reactions entail excitotoxicity and thus harm neuronal function. The release of glutamate via the antiporter system xc- is accompanied by the import of cystine-an amino acid essential in the antioxidant glutathione. This homeostasis between excitotoxicity and intracellular antioxidant response is plastic and off-balance in central nervous system (CNS) diseases. System xc- is highly expressed on glioma cells and sensitizes them to ferroptotic cell death. Hence, system xc- is a potential target for chemotherapeutic add-on therapy. Recent research reveals a pivotal role of system xc- and EAAT1/2 in tumor-associated and other types of epilepsy. Numerous studies show that in Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease, these glutamate transporters are dysregulated-and disease mechanisms could be interposed by targeting system xc- and EAAT1/2. Interestingly, in neuroinflammatory diseases such as multiple sclerosis, there is growing evidence for glutamate transporter involvement. Here, we propose that the current knowledge strongly suggest a benefit from rebalancing glial transporters during treatment.

Keywords:  Alzheimer's disease; GLAST; GLT-1; Parkinson's disease; SLC7A11; amyotrophic lateral sclerosis; glioma; neuroinflammation

DOI:  https://doi.org/10.31083/j.fbl2803057
Ir Med J. 2023 Mar 23. 116(3): 743

Medium Chain Acyl-CoA Dehydrogenase Deficiency: 3 years of Newborn Screening.

C Howard, I Gorman, E Crushell, I Knerr, J Hughes, R Boruah, L O'Grady, M Y Elsammak, J J Brady, A A Monavari.
Front Mol Neurosci. 2023 ;16 1117146

Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense.

Mastura Akter, Haiying Ma, Mahadi Hasan, Anwarul Karim, Xiaowei Zhu, Liang Zhang, Ying Li.

  L-lactate plays a critical role in learning and memory. Studies in rats showed that administration of exogenous L-lactate into the anterior cingulate cortex and hippocampus (HPC) improved decision-making and enhanced long-term memory formation, respectively. Although the molecular mechanisms by which L-lactate confers its beneficial effect are an active area of investigations, one recent study found that L-lactate supplementation results in a mild reactive oxygen species burst and induction of pro-survival pathways. To further investigate the molecular changes induced by L-lactate, we injected rats with either L-lactate or artificial CSF bilaterally into the dorsal HPC and collected the HPC after 60 minutes for mass spectrometry. We identified increased levels of several proteins that include SIRT3, KIF5B, OXR1, PYGM, and ATG7 in the HPC of the L-lactate treated rats. SIRT3 (Sirtuin 3) is a key regulator of mitochondrial functions and homeostasis and protects cells against oxidative stress. Further experiments identified increased expression of the key regulator of mitochondrial biogenesis (PGC-1α) and mitochondrial proteins (ATPB, Cyt-c) as well as increased mitochondrial DNA (mtDNA) copy number in the HPC of L-lactate treated rats. OXR1 (Oxidation resistance protein 1) is known to maintain mitochondrial stability. It mitigates the deleterious effects of oxidative damage in neurons by inducing a resistance response against oxidative stress. Together, our study suggests that L-lactate can induce expression of key regulators of mitochondrial biogenesis and antioxidant defense. These findings create new research avenues to explore their contribution to the L-lactate's beneficial effect in cognitive functions as these cellular responses might enable neurons to generate more ATP to meet energy demand of neuronal activity and synaptic plasticity as well as attenuate the associated oxidative stress.

Keywords:  PGC-1 alpha; SIRT3; hippocampus; lactate; mitochondrial biogenesis; oxidative stress; proteomics

DOI:  https://doi.org/10.3389/fnmol.2023.1117146
J Lipid Res. 2023 Apr 01. pii: S0022-2275(23)00040-8. [Epub ahead of print] 100367

Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization.

Yue Huang, Wenbin Zhang, Xiaorou Guo, Ying Zhang, Junfeng Wu, Hengbing Zu.

  For the past 20 years, the majority of cell culture studies reported that increasing cholesterol level increases amyloid-β (Aβ) production. Conversely, other studies and genetic evidences support that cellular cholesterol loss leads to Aβ generation. As a highly controversial issue in Alzheimer's disease (AD) pathogenesis，the apparent contradiction prompted us to again explore the role of cellular cholesterol in Aβ production. Here, we adopted new neuronal and astrocytic cell models induced by 3β-hydroxysterol-Δ24 reductase (DHCR24), which obviously differ from the widely used cell models with overexpressing amyloid precursor protein (APP) in the majority of previous studies. In neuronal and astrocytic cell model, we found that deficiency of cellular cholesterol by DHCR24 knock-down obviously increased intracellular and extracellular Aβ generation. Importantly, in cell models with overexpressing APP, we found that APP overexpression could disrupt cellular cholesterol homeostasis and affect function of cells, coupled with the increase of APP β-cleavage product, 99-residue transmembrane C-terminal domain (C99). Therefore, we suppose the results derived from the APP knock-in models will need to be re-evaluated. One rational explanation for the discrepancy between our outcomes and the previous studies could be attributed to the two different cell models. Mechanistically, we showed that cellular cholesterol loss obviously altered APP intracellular localization by affecting cholesterol-related trafficking protein of APP. Therefore, our outcomes strongly support cellular cholesterol loss by DHCR24 knockdown leads to Aβ production.

Keywords:  APP; Alzheimer’s disease; Amyloid-β; Cholesterol; DHCR24; Pathogenesis

DOI:  https://doi.org/10.1016/j.jlr.2023.100367
Acta Neuropathol Commun. 2023 Mar 31. 11(1): 54

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer's disease brain.

Wenzhang Wang, Fanpeng Zhao, Yubing Lu, Sandra L Siedlak, Hisashi Fujioka, Hao Feng, George Perry, Xiongwei Zhu.

  Loss of synapses is the most robust pathological correlate of Alzheimer's disease (AD)-associated cognitive deficits, although the underlying mechanism remains incompletely understood. Synaptic terminals have abundant mitochondria which play an indispensable role in synaptic function through ATP provision and calcium buffering. Mitochondrial dysfunction is an early and prominent feature in AD which could contribute to synaptic deficits. Here, using electron microscopy, we examined synapses with a focus on mitochondrial deficits in presynaptic axonal terminals and dendritic spines in cortical biopsy samples from clinically diagnosed AD and age-matched non-AD control patients. Synaptic vesicle density within the presynaptic axon terminals was significantly decreased in AD cases which appeared largely due to significantly decreased reserve pool, but there were significantly more presynaptic axons containing enlarged synaptic vesicles or dense core vesicles in AD. Importantly, there was reduced number of mitochondria along with significantly increased damaged mitochondria in the presynapse of AD which correlated with changes in SV density. Mitochondria in the post-synaptic dendritic spines were also enlarged and damaged in the AD biopsy samples. This study provided evidence of presynaptic vesicle loss as synaptic deficits in AD and suggested that mitochondrial dysfunction in both pre- and post-synaptic compartments contribute to synaptic deficits in AD.

Keywords:  Alzheimer disease; Dendritic spine; Dense core vesicle; Mitochondria; Synapse; Synaptic vesicles

DOI:  https://doi.org/10.1186/s40478-023-01552-7
NMR Biomed. 2023 Apr 03. e4946

Neonatal hyperbilirubinemia differentially alters the neurochemical profiles of the developing cerebellum and hippocampus in a preterm Gunn rat model.

Katherine M Satrom, Raghavendra B Rao, Ivan Tkáč.

  Neonatal hyperbilirubinemia (NHB) can lead to brain injury in newborn infants by affecting specific regions including the cerebellum and hippocampus. Extremely preterm infants (EPT) are more vulnerable to bilirubin neurotoxicity, but the mechanism and extent of injury is not well understood. A preterm version of Gunn rat model was utilized to investigate severe preterm NHB. Homozygous/jaundiced Gunn rat pups were injected (i.p.) on postnatal day (P) 5 with sulfadimethoxine, which increases serum free bilirubin capable of crossing blood brain barrier and causing brain injury. The neurochemical profiles of the cerebellum and hippocampus were determined using in vivo 1 H MRS at 9.4T on P30 and compared with heterozygous/non-jaundiced control rats. Transcript expression of related genes were determined by real-time quantitative PCR. MRI revealed significant morphological changes in the cerebellum of jaundiced rats. The concentrations of myo-inositol (+54%), glucose (+51%), N-acetylaspartylglutamate (+21%), and the sum of glycerophosphocholine and phosphocholine (+17%) were significantly higher in cerebellum of the jaundiced group compared with control group. Despite the lack of morphologic changes in the hippocampus, the concentration of myo-inositol (+9%) was higher and the concentration of creatine (-8%) and of total creatine (-3%) were lower in the jaundiced group. In the hippocampus, expression of calcium/calmodulin dependent protein kinase II alpha (Camk2a), glucose transporter (Glut) 1, and Glut3 transcripts were downregulated in the jaundiced group. In the cerebellum, the expression of glial fibrillary acidic protein (Gfap), myelin basic protein (Mbp), and Glut1 transcript expression was upregulated in the jaundiced group. These results indicate osmotic imbalance, gliosis, changes in energy utilization and myelination and demonstrate that preterm NHB critically affects brain development in a region-specific manner, with the cerebellum more severely impacted than the hippocampus.

Keywords:  Cerebellum; Gunn Rat; Hippocampus; Hyperbilirubinemia; MR Spectroscopy; Neurochemical Profile; Preterm Infant

DOI:  https://doi.org/10.1002/nbm.4946
Prostaglandins Leukot Essent Fatty Acids. 2023 Mar 22. pii: S0952-3278(23)00037-6. [Epub ahead of print]192 102568

Analysis of fatty acid composition and sensitivity to dietary n-3 PUFA intervention of mouse n-3 PUFA-enriched tissues/organs.

Hui Zhang, Yannan He, Chunyan Song, Zhenglong Chai, Chundi Liu, Shuben Sun, Qiuhan Huang, Canxia He, Xiaohong Zhang, Yuping Zhou, Feng Zhao.

  PURPOSE: n-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA; C22:6 n3) and eicosapentaenoic acid (EPA; C20:5 n3), are of concern for their health-promoting effects such as anti-inflammatory, but the tissue selectivity for n-3 PUFA (i.e., which tissues and organs are rich in n-3 PUFA) is still not well known. In addition, it is unclear which tissues and organs are more sensitive to n-3 PUFA intervention. These unresolved issues have greatly hindered the exploring of the health benefits of n-3 PUFA.METHODS: Twenty-four 7-week-old male C57BL/6 J mice were assigned to the control, fish oil, DHA, and EPA groups. The last three groups were given a 4-week oral intervention of fatty acids in ethyl ester (400 mg/kg bw). The fatty acid profiles in 27 compartments were determined by gas chromatography.
RESULTS: The proportion of long-chain n-3 PUFA (the total relative percentage of EPA, DPA n3, and DHA) was analyzed. Eight tissues and organs, including the brain (cerebral cortex, hippocampus, hypothalamus) and peripheral organs (tongue, quadriceps, gastrocnemius, kidney, and heart) were determined as being n-3 PUFA-enriched tissues and organs, owing to their high n-3 PUFA levels. The highest n-3 PUFA content was observed in the tongue for the first time. Notably, the content of linoleic acid (LA; C18:2 n6c) in peripheral organs was observed to be relatively high compared with that in the brain. Interestingly, the proportions of EPA in the kidney, heart, quadriceps, gastrocnemius, and tongue increased more markedly after the EPA intervention than after the DHA or fish oil intervention. As expected, the levels of proinflammatory arachidonic acid (AA; C20:4 n6) in the kidney, quadriceps, and tongue were markedly decreased after the three dietary interventions.
CONCLUSION: Peripheral tissues and organs, including the tongue, quadriceps, gastrocnemius, kidney, and heart, besides the brain, showed obvious tissue selectivity for n-3 PUFA. In the whole body of mice, the tongue exhibits the strongest preference for n-3 PUFA, with the highest proportion of n-3 PUFA. Moreover, these peripheral tissues and organs, especially the kidney, are more sensitive to dietary EPA administration in comparison with the brain.

Keywords:  Dietary intervention; Docosahexaenoic acid; Eicosapentaenoic acid; Fatty acid composition; Tissue selectivity of fatty acids; n-3 PUFA

DOI:  https://doi.org/10.1016/j.plefa.2023.102568
NPJ Parkinsons Dis. 2023 Apr 07. 9(1): 55

Neuroprotective actions of a fatty acid nitroalkene in Parkinson's disease.

Roberto Di Maio, Matthew T Keeney, Veronika Cechova, Amanda Mortimer, Ahssan Sekandari, Pascal Rowart, J Timothy Greenamyre, Bruce A Freeman, Marco Fazzari.

To date there are no therapeutic strategies that limit the progression of Parkinson's disease (PD). The mechanisms underlying PD-related nigrostriatal neurodegeneration remain incompletely understood, with multiple factors modulating the course of PD pathogenesis. This includes Nrf2-dependent gene expression, oxidative stress, α-synuclein pathology, mitochondrial dysfunction, and neuroinflammation. In vitro and sub-acute in vivo rotenone rat models of PD were used to evaluate the neuroprotective potential of a clinically-safe, multi-target metabolic and inflammatory modulator, the electrophilic fatty acid nitroalkene 10-nitro-oleic acid (10-NO2-OA). In N27-A dopaminergic cells and in the substantia nigra pars compacta of rats, 10-NO2-OA activated Nrf2-regulated gene expression and inhibited NOX2 and LRRK2 hyperactivation, oxidative stress, microglial activation, α-synuclein modification, and downstream mitochondrial import impairment. These data reveal broad neuroprotective actions of 10-NO2-OA in a sub-acute model of PD and motivate more chronic studies in rodents and primates.

DOI: https://doi.org/10.1038/s41531-023-00502-3
Sci Rep. 2023 Apr 06. 13(1): 5665

Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease.

Sarah Kim, Kathleen Ochoa, Sierra E Melli, Fawad A K Yousufzai, Zerian D Barrera, Aela A Williams, Gianna McIntyre, Esteban Delgado, James N Bolish, Collin M Macleod, Mary Boghos, Hayden P Lens, Alex G Ramos, Vincent B Wilson, Kelly Maloney, Zachary M Padron, Amaal H Khan, Rosa E Blanco, Ileana Soto.

Purkinje cell (PC) loss occurs at an early age in patients and animal models of Niemann-Pick Type C (NPC), a lysosomal storage disease caused by mutations in the Npc1 or Npc2 genes. Although degeneration of PCs occurs early in NPC, little is known about how NPC1 deficiency affects the postnatal development of PCs. Using the Npc1nmf164 mouse model, we found that NPC1 deficiency significantly affected the postnatal development of PC dendrites and synapses. The developing dendrites of Npc1nmf164 PCs were significantly deficient in mitochondria and lysosomes. Furthermore, anabolic (mTORC1) and catabolic (TFEB) signaling pathways were not only perturbed but simultaneously activated in NPC1-deficient PCs, suggesting a loss of metabolic balance. We also found that mice with conditional heterozygous deletion of the Phosphatase and Tensin Homolog Deleted on Chromosome 10 gene (Pten-cHet), an inhibitor of mTORC1, showed similar early dendritic alterations in PCs to those found in Npc1-deficient mice. However, in contrast to Npc1nmf164 mice, Pten-cHet mice exhibited the overactivation of the mTORC1 pathway but with a strong inhibition of TFEB signaling, along with no dendritic mitochondrial reductions by the end of their postnatal development. Our data suggest that disruption of the lysosomal-metabolic signaling in PCs causes dendritic and synaptic developmental deficits that precede and promote their early degeneration in NPC.

DOI: https://doi.org/10.1038/s41598-023-32971-0
Front Mol Neurosci. 2023 ;16 1078634

Severe neurometabolic phenotype in npc1 -/- zebrafish with a C-terminal mutation.

Ana Quelle-Regaldie, Nerea Gandoy-Fieiras, Paula Rodríguez-Villamayor, Sandra Maceiras, Ana Paula Losada, Mónica Folgueira, Pablo Cabezas-Sáinz, Antón Barreiro-Iglesias, María Villar-López, María Isabel Quiroga-Berdeal, Laura Sánchez, María Jesús Sobrido.

  Niemann Pick disease type C (NPC) is an autosomal recessive neurodegenerative lysosomal disorder characterized by an accumulation of lipids in different organs. Clinical manifestations can start at any age and include hepatosplenomegaly, intellectual impairment, and cerebellar ataxia. NPC1 is the most common causal gene, with over 460 different mutations with heterogeneous pathological consequences. We generated a zebrafish NPC1 model by CRISPR/Cas9 carrying a homozygous mutation in exon 22, which encodes the end of the cysteine-rich luminal loop of the protein. This is the first zebrafish model with a mutation in this gene region, which is frequently involved in the human disease. We observed a high lethality in npc1 mutants, with all larvae dying before reaching the adult stage. Npc1 mutant larvae were smaller than wild type (wt) and their motor function was impaired. We observed vacuolar aggregations positive to cholesterol and sphingomyelin staining in the liver, intestine, renal tubules and cerebral gray matter of mutant larvae. RNAseq comparison between npc1 mutants and controls showed 284 differentially expressed genes, including genes with functions in neurodevelopment, lipid exchange and metabolism, muscle contraction, cytoskeleton, angiogenesis, and hematopoiesis. Lipidomic analysis revealed significant reduction of cholesteryl esters and increase of sphingomyelin in the mutants. Compared to previously available zebrafish models, our model seems to recapitulate better the early onset forms of the NPC disease. Thus, this new model of NPC will allow future research in the cellular and molecular causes/consequences of the disease and on the search for new treatments.

Keywords:  Niemann Pick; genetic edition; lipid accumulation; neurodegeneration; zebrafish

DOI:  https://doi.org/10.3389/fnmol.2023.1078634
Front Genet. 2023 ;14 1109547

Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system.

Emily M Spelbrink, Tanya L Brown, Elise Brimble, Kirsten A Blanco, Kimberly L Nye, Brenda E Porter.

  Introduction: SLC13A5 citrate transporter disorder is a rare autosomal recessive genetic disease that has a constellation of neurologic symptoms. To better characterize the neurologic and clinical laboratory phenotype, we utilized patient medical records collected by Ciitizen, an Invitae company, with support from the TESS Research Foundation. Methods: Medical records for 15 patients with a suspected genetic and clinical diagnosis of SLC13A5 citrate transporter disorder were collected by Ciitizen, an Invitae company. Genotype, clinical phenotypes, and laboratory data were extracted and analyzed. Results: The 15 patients reported all had epilepsy and global developmental delay. Patients continued to attain motor milestones, though much later than their typically developing peers. Clinical diagnoses support abnormalities in communication, and low or mixed tone with several movement disorders, including, ataxia and dystonia. Serum citrate was elevated in the 3 patients in whom it was measured; other routine laboratory studies assessing renal, liver and blood function had normal values or no consistent abnormalities. Many electroencephalograms (EEGs) were performed (1 to 35 per patient), and most but not all were abnormal, with slowing and/or epileptiform activity. Fourteen of the patients had one or more brain magnetic resonance imaging (MRI) reports: 7 patients had at least one normal brain MRI, but not with any consistent findings except white matter signal changes. Discussion: These results show that in addition to the epilepsy phenotype, SLC13A5 citrate transporter disorder impacts global development, with marked abnormalities in motor abilities, tone, coordination, and communication skills. Further, utilizing cloud-based medical records allows industry, academic, and patient advocacy group collaboration to provide preliminary characterization of a rare genetic disorder. Additional characterization of the neurologic phenotype will be critical to future study and developing treatment for this and related rare genetic disorders.

Keywords:  NACT; SLC13A5; citrate; developmental delay; epilepsy; movement disorder; rare disease; transporter

DOI:  https://doi.org/10.3389/fgene.2023.1109547
Mol Oncol. 2023 Apr 04.

Targeting mitochondrial energetics reverses panobinostat- and marizomib-induced resistance in pediatric and adult high-grade gliomas.

Esther P Jane, Matthew C Reslink, Taylor Gatesman, Matthew Halbert, Tracy A Miller, Brian J Golbourn, Stephanie M Casillo, Steven J Mullett, Stacy G Wendell, Udochukwu Obodo, Dinesh Mohanakrishnan, Riya Dange, Antony Michealraj, Charles Brenner, Sameer Agnihotri, Daniel R Premkumar, Ian F Pollack.

  In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and the proteasomal inhibitor bortezomib displayed synergistic therapeutic activity against pediatric and adult high-grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain-penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) were employed to compare the molecular signatures enriched in resistant compared to drug-naïve cells. The levels of adenosine 5'-triphosphate (ATP), nicotinamide adenine dinucleotide (NAD)+ content, hexokinase activity and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD+ content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small-molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat- and marizomib-resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.

Keywords:  Glioma; OXPHOS; marizomib; mitochondria; panobinostat; resistance

DOI:  https://doi.org/10.1002/1878-0261.13427
Am J Clin Nutr. 2023 Apr 05. pii: S0002-9165(23)46320-4. [Epub ahead of print]

The relationship of omega-3 fatty acids with dementia and cognitive decline: evidence from perspective cohort studies of supplementation, dietary intake, and blood markers.

Alzheimer’s Disease Neuroimaging Initiative

  BACKGROUND: Previous data have linked omega-3 fatty acid with risk of dementia.OBJECTIVES: To assess the longitudinal relationships of omega-3 polyunsaturated fatty acids intake as well as blood biomarkers with the risk of Alzheimer's disease (AD), dementia or cognitive decline.
METHODS: Longitudinal data were derived from 1,135 participants without dementia (mean age = 73 years) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to evaluate the associations of omega-3 fatty acid supplementation and blood biomarkers with incident AD during 6-year follow-up. A meta-analysis of published cohort studies was further conducted to test the longitudinal relationships of dietary intake of omega-3 and its peripheral markers with all-cause dementia or cognitive decline. Causal dose-response analyses were conducted using the robust error meta-regression model.
RESULTS: In the ADNI cohort, long-term users of omega-3 fatty acid supplements exhibited a 64% reduced risk of AD (adjusted hazard ratio = 0.36, 95% confidence interval [CI] = 0.54 to 0.96, p = 0.005). After incorporating 48 longitudinal studies involving 103,651 participants, moderate-to-high level of evidence suggested that dietary intake of omega-3 fatty acids could lower the risk of all-cause dementia or cognitive decline by ∼20% , especially for DHA intake (Relative risk [RR] = 0.82, I2 =63.6%, p = 0.001) and for studies that adjusted for APOE ε4 status (RR = 0.83, I2 =65%, p = 0.006). Each increment of 0.1 g per day of DHA or EPA intake was associated with an 8%∼9.9% (Plinear < 0.0005) lower risk of cognitive decline. Moderate-to-high levels of evidence indicated that elevated levels of plasma EPA (RR = 0.86, I2 =38.9%) and erythrocyte membrane DHA (RR = 0.94, I2 =0.4%) was associated with a lower risk of cognitive decline.
CONCLUSIONS: Dietary intake or long-term supplementation of omega-3 fatty acid may help reduce the risk of AD or cognitive decline.

Keywords:  AD; Biomarker; Cognitive decline; Dementia; Dietary; Omega-3 fatty acid

DOI:  https://doi.org/10.1016/j.ajcnut.2023.04.001
Nat Commun. 2023 Apr 06. 14(1): 1930

Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.

Pascale Baden, Maria Jose Perez, Hariam Raji, Federico Bertoli, Stefanie Kalb, María Illescas, Fokion Spanos, Claudio Giuliano, Alessandra Maria Calogero, Marvin Oldrati, Hannah Hebestreit, Graziella Cappelletti, Kathrin Brockmann, Thomas Gasser, Anthony H V Schapira, Cristina Ugalde, Michela Deleidi.

Mutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.

DOI: https://doi.org/10.1038/s41467-023-37454-4