Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model.

Misfolded wild-type superoxide dismutase 1 (disSOD1) protein is implicated in the death of substantia nigra (SN) dopamine neurons in Parkinson disease. Regionally reduced copper availability, and subsequent reduced copper binding to SOD1, is a key factor driving the development of this pathology, suggesting brain copper supplementation may constitute an effective means of preventing its formation. We evaluated whether the blood-brain-barrier-permeable copper delivery drug, CuATSM, attenuated the misfolding and deposition of wild-type disSOD1 and associated neuron death in a novel mouse model that expresses this pathology.

Aspartate in the Brain: A Review.

L-Aspartate (aspartic acid; CHNO; 2-aminobutanedoic acid) is a non-essential α-amino acid found ubiquitously throughout the body, including in the brain. Aspartate is one of the protein-forming amino acids and the formation of tRNA-aspartate complex is catalysed by aspartyl tRNA synthetase. Free aspartate, which is the main subject of this review, plays key roles in metabolism, as an amino donor and acceptor.

Parkinson-like wild-type superoxide dismutase 1 pathology induces nigral dopamine neuron degeneration in a novel murine model.

Atypical wild-type superoxide dismutase 1 (SOD1) protein misfolding and deposition occurs specifically within the degenerating substantia nigra pars compacta (SNc) in Parkinson disease. Mechanisms driving the formation of this pathology and relationship with SNc dopamine neuron health are yet to be fully understood. We applied proteomic mass spectrometry and synchrotron-based biometal quantification to post-mortem brain tissues from the SNc of Parkinson disease patients and age-matched controls to uncover key factors underlying the formation of wild-type SOD1 pathology in this disorder.

Brain energy metabolism: A roadmap for future research.

Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation.

Correction to: L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism.

The original version of this published article, the bottom right hand panels of Figs. 3-6 were labelled as "Isotopomers formed from [1-C]D-glucose". This is incorrect and should read "Isotopomers formed from [1,2-C]acetate".

L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism.

L-Ornithine-L-aspartate (LOLA), a crystalline salt, is used primarily in the management of hepatic encephalopathy. The degree to which it might penetrate the brain, and the effects it might have on metabolism in brain are poorly understood. Here, to investigate the effects of LOLA on brain energy metabolism we incubated brain cortical tissue slices from guinea pig (Cavea porcellus) with the constituent amino acids of LOLA, L-ornithine or L-aspartate, as well as LOLA, in the presence of [1-C]D-glucose and [1,2-C]acetate; these labelled substrates are useful indicators of brain metabolic activity.

Actions of Alcohol in Brain: Genetics, Metabolomics, GABA Receptors, Proteomics and Glutamate Transporter GLAST/EAAT1.

We present an overview of genetic, metabolomic, proteomic and neurochemical studies done mainly in our laboratories that could improve prediction, mechanistic understanding and possibly extend to diagnostics and treatment of alcoholism and alcohol addiction. Specific polymorphisms in genes encoding for interleukins 2 and 6, catechol-O-methyl transferase (COMT), monaminooxidase B (MAO B) and several other enzymes were identified as associated with altered risks of alcoholism in humans. A polymorphism in the gene for BDNF has been linked to the risk of developing deficiences in colour vision sometimes observed in alcoholics.

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy.

N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease-a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations.

β-Hydroxybutyrate Boosts Mitochondrial and Neuronal Metabolism but is not Preferred Over Glucose Under Activated Conditions.

The ketone body, β-hydroxybutyrate (βOHB), is metabolised by the brain alongside the mandatory brain fuel glucose. To examine the extent and circumstances by which βOHB can supplement glucose metabolism, we studied guinea pig cortical brain slices using increasing concentrations of [U-C]D-βOHB in conjunction with [1-C]D-glucose under conditions of normo- and hypoglycaemia, as well as under high potassium (40 mmol/L K) depolarization in normo- and hypoglycaemic conditions. The contribution of βOHB to synthesis of GABA was also probed by inhibiting the synthesis of glutamine, a GABA precursor, with methionine sulfoximine (MSO).

Acetate metabolism does not reflect astrocytic activity, contributes directly to GABA synthesis, and is increased by silent information regulator 1 activation.

[ C]Acetate is known to label metabolites preferentially in astrocytes rather than neurons and it has consequently been used as a marker for astrocytic activity. Recent discoveries suggest that control of acetate metabolism and its contributions to the synthesis of metabolites in brain is not as simple as first thought. Here, using a Guinea pig brain cortical tissue slice model metabolizing [1- C]D-glucose and [1,2- C]acetate, we investigated control of acetate metabolism and the degree to which it reflects astrocytic activity.

Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling.

Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure.

Silent information regulator 1 modulator resveratrol increases brain lactate production and inhibits mitochondrial metabolism, whereas SRT1720 increases oxidative metabolism.

Silent information regulators (SIRTs) have been shown to deacetylate a range of metabolic enzymes, including those in glycolysis and the Krebs cycle, and thus alter their activity. SIRTs require NAD(+) for their activity, linking cellular energy status to enzyme activity. To examine the impact of SIRT1 modulation on oxidative metabolism, this study tests the effect of ligands that are either SIRT-activating compounds (resveratrol and SRT1720) or SIRT inhibitors (EX527) on the metabolism of (13)C-enriched substrates by guinea pig brain cortical tissue slices with (13)C and (1)H nuclear magnetic resonance spectroscopy.

Metabolomic Approaches to Defining the Role(s) of GABAρ Receptors in the Brain.

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) acts through various types of receptors in the central nervous system. GABAρ receptors, defined by their characteristic pharmacology and presence of ρ subunits in the channel structure, are poorly understood and their role in the cortex is ill-defined. Here, we used a targeted pharmacological, NMR-based functional metabolomic approach in Guinea pig brain cortical tissue slices to identify a distinct role for these receptors.

Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations.

Ethanol is a known neuromodulatory agent with reported actions at a range of neurotransmitter receptors. Here, we measured the effect of alcohol on metabolism of [3-¹³C]pyruvate in the adult Guinea pig brain cortical tissue slice and compared the outcomes to those from a library of ligands active in the GABAergic system as well as studying the metabolic fate of [1,2-¹³C]ethanol. Analyses of metabolic profile clusters suggest that the significant reductions in metabolism induced by ethanol (10, 30 and 60 mM) are via action at neurotransmitter receptors, particularly α4β3δ receptors, whereas very low concentrations of ethanol may produce metabolic responses owing to release of GABA via GABA transporter 1 (GAT1) and the subsequent interaction of this GABA with local α5- or α1-containing GABA(A)R.