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Background: PolyQ diseases are autosomal dominant neurodegenerative disorders caused by the expansion of CAG repeats. While of slow progression, these diseases are ultimately fatal and lack effective therapies., Methods: A high-throughput chemical screen was conducted to identify drugs that lower the toxicity of a protein containing the first exon of Huntington's disease (HD) protein huntingtin (HTT) harbouring 94 glutamines (Htt-Q 94 ). Candidate drugs were tested in a wide range of in vitro and in vivo models of polyQ toxicity., Findings: The chemical screen identified the anti-leprosy drug clofazimine as a hit, which was subsequently validated in several in vitro models. Computational analyses of transcriptional signatures revealed that the effect of clofazimine was due to the stimulation of mitochondrial biogenesis by peroxisome proliferator-activated receptor gamma (PPARγ). In agreement with this, clofazimine rescued mitochondrial dysfunction triggered by Htt-Q 94 expression. Importantly, clofazimine also limited polyQ toxicity in developing zebrafish and neuron-specific worm models of polyQ disease., Interpretation: Our results support the potential of repurposing the antimicrobial drug clofazimine for the treatment of polyQ diseases., Funding: A full list of funding sources can be found in the acknowledgments section., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways involved in glutamine catabolism, anabolism, and glutamine-glutamate cycling. In recent years, altered glutamine metabolism has been found to play important roles in the pathologic consequences of mitochondrial dysfunction. Glutamine is a pleiotropic molecule, not only providing an alternate carbon source to glucose in certain conditions, but also playing unique roles in cellular communication in neurons and astrocytes. Glutamine consumption and catabolic flux can be significantly altered in settings of genetic mitochondrial defects or exposure to mitochondrial toxins, and alterations to glutamine metabolism appears to play a particularly significant role in neurodegenerative diseases. These include primary mitochondrial diseases like Leigh syndrome (subacute necrotizing encephalopathy) and MELAS (mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke-like episodes), as well as complex age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Pharmacologic interventions targeting glutamine metabolizing and catabolizing pathways appear to provide some benefits in cell and animal models of these diseases, indicating glutamine metabolism may be a clinically relevant target. In this review, we discuss glutamine metabolism, mitochondrial disease, the impact of mitochondrial dysfunction on glutamine metabolic processes, glutamine in neurodegeneration, and candidate targets for therapeutic intervention. • Altered glutamine metabolism has been linked to diseases arising from mitochondrial dysfunction. • Glutamine metabolism is linked to neurodegenerative processes. • Interventions targeting glutamine metabolism, directly or indirectly, have shown some promise in pre-clinical studies. [ABSTRACT FROM AUTHOR]

A 49-year-old Japanese man had shown developmental delay, learning difficulties, epilepsy, and slowly progressive gait disturbance in elementary school. At 46 years old, he experienced repeated drowsiness with or without generalized convulsions, and hyperammonemia was detected. Brain magnetic resonance imaging detected multiple cerebral white matter lesions. An electroencephalogram showed diffuse slow basic activities with 2- to 3-Hz δ waves. Genetic tests confirmed a diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Leukoencephalopathy was resolved following the administration of L-arginine and lactulose with a decrease in plasma ammonia levels and glutamine-glutamate peak on magnetic resonance spectroscopy. Leukoencephalopathy in HHH syndrome may be reversible with the resolution of hyperammonemia-induced glutamine toxicity.

L-γ-Glutamyl-p-nitroanilide (GPNA) is widely used to inhibit the glutamine (Gln) transporter ASCT2, but recent studies have demonstrated that it is also able to inhibit other sodium-dependent and independent amino acid transporters. Moreover, GPNA is a well known substrate of the enzyme γ-glutamyltransferase (GGT). Our aim was to evaluate the effect of GGT-mediated GPNA catabolism on cell viability and Gln transport. The GGT-catalyzed hydrolysis of GPNA produced cytotoxic effects in lung cancer A549 cells, resulting from the release of metabolite p-nitroaniline (PNA) rather than from the inhibition of Gln uptake. Interestingly, compounds like valproic acid, verapamil and reversan were able to increase the cytotoxicity of GPNA and PNA, suggesting a key role of intracellular detoxification mechanisms. Our data indicate that the mechanism of action of GPNA is more complex than believed, and further confirm the poor specificity of GPNA as an inhibitor of Gln transport. Different factors may modulate the final effects of GPNA, ranging from GGT and ASCT2 expression to intracellular defenses against xenobiotics. Thus, other strategies - such as a genetic suppression of ASCT2 or the identification of new specific inhibitors - should be preferred when inhibition of ASCT2 function is required.

Background: Glutamate-induced excitotoxicity, oxidative damage, and neuroinflammation are believed to play an important role in the development of a number of CNS disorders. We recently reported that a high dose of glutamate could induce AMPK-mediated neurodegeneration in the postnatal day 7 (PND7) rat brain. Yet, the mechanism of glutamate-induced oxidative stress and neuroinflammation in the postnatal brain is not well understood. Here, we report for the first time the mechanism of glutamate-induced oxidative damage, neuroinflammation, and neuroprotection by polyphenolic anthocyanins in PND7., Methods: PND7 rat brains, SH-SY5Y, and BV2 cells treated either alone with glutamate or in combination with anthocyanins and compound C were examined with Western blot and immunofluorescence techniques. Additionally, reactive oxygen species (ROS) assay and other ELISA kit assays were employed to know the therapeutic efficacy of anthocyanins against glutamate., Results: A single injection of glutamate to developing rats significantly increased brain glutamate levels, activated and phosphorylated AMPK induction, and inhibited nuclear factor-E2-related factor 2 (Nrf2) after 2, 3, and 4 h in a time-dependent manner. In contrast, anthocyanin co-treatment significantly reduced glutamate-induced AMPK induction, ROS production, neuroinflammation, and neurodegeneration in the developing rat brain. Most importantly, anthocyanins increased glutathione (GSH and GSSG) levels and stimulated the endogenous antioxidant system, including Nrf2 and heme oxygenase-1 (HO-1), against glutamate-induced oxidative stress. Interestingly, blocking AMPK with compound C in young rats abolished glutamate-induced neurotoxicity. Similarly, all these experiments were replicated in SH-SY5Y cells by silencing AMPK with siRNA, which suggests that AMPK is the key mediator in glutamate-induced neurotoxicity., Conclusions: Here, we report for the first time that anthocyanins can potentially decrease glutamate-induced neurotoxicity in young rats. Our work demonstrates that glutamate is toxic to the developing rat brain and that anthocyanins can minimize the severity of glutamate-induced neurotoxicity in an AMPK-dependent manner.