{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T01:15:15Z","timestamp":1782954915205,"version":"3.54.5"},"reference-count":82,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T00:00:00Z","timestamp":1693180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000691","name":"Academy of Medical Sciences","doi-asserted-by":"publisher","award":["SBF006\\1168"],"award-info":[{"award-number":["SBF006\\1168"]}],"id":[{"id":"10.13039\/501100000691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterised by progressive degeneration of the motor neurones. An expanded GGGGCC (G4C2) hexanucleotide repeat in C9orf72 is the most common genetic cause of ALS and frontotemporal dementia (FTD); therefore, the resulting disease is known as C9ALS\/FTD. Here, we employ a Drosophila melanogaster model of C9ALS\/FTD (C9 model) to investigate a role for specific medium-chain fatty acids (MCFAs) in reversing pathogenic outcomes. Drosophila larvae overexpressing the ALS-associated dipeptide repeats (DPRs) in the nervous system exhibit reduced motor function and neuromuscular junction (NMJ) defects. We show that two MCFAs, nonanoic acid (NA) and 4-methyloctanoic acid (4-MOA), can ameliorate impaired motor function in C9 larvae and improve NMJ degeneration, although their mechanisms of action are not identical. NA modified postsynaptic glutamate receptor density, whereas 4-MOA restored defects in the presynaptic vesicular release. We also demonstrate the effects of NA and 4-MOA on metabolism in C9 larvae and implicate various metabolic pathways as dysregulated in our ALS model. Our findings pave the way to identifying novel therapeutic targets and potential treatments for ALS.<\/jats:p>","DOI":"10.3390\/cells12172163","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T08:35:05Z","timestamp":1693298105000},"page":"2163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Medium-Chain Fatty Acids Rescue Motor Function and Neuromuscular Junction Degeneration in a Drosophila Model of Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"12","author":[{"given":"Ella","family":"Dunn","sequence":"first","affiliation":[{"name":"Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 OEX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1640-0845","authenticated-orcid":false,"given":"Joern R.","family":"Steinert","sequence":"additional","affiliation":[{"name":"Faculty of Medicine & Health Sciences, Queen\u2019s Medical Centre, Nottingham NG7 2UH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aelfwin","family":"Stone","sequence":"additional","affiliation":[{"name":"Faculty of Medicine & Health Sciences, Queen\u2019s Medical Centre, Nottingham NG7 2UH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virender","family":"Sahota","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 OEX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9826-6020","authenticated-orcid":false,"given":"Robin S. B.","family":"Williams","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 OEX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Snowden","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 OEX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hrvoje","family":"Augustin","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 OEX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,28]]},"reference":[{"key":"ref_1","unstructured":"Barbieri, E. (2023, July 25). Epidemiology of ALS: Incidence, Prevalence, and Suspected Clusters. TargetALS.org 2022. Available online: https:\/\/www.targetals.org\/2022\/11\/22\/epidemiology-of-als-incidence-prevalence-and-clusters\/."},{"key":"ref_2","first-page":"S320","article-title":"Amyotrophic lateral sclerosis: Disease state overview","volume":"24","author":"Hulisz","year":"2018","journal-title":"Am. J. Manag. Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17085","DOI":"10.1038\/nrdp.2017.85","article-title":"Amyotrophic lateral sclerosis","volume":"3","author":"Hardiman","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/S0140-6736(10)61156-7","article-title":"Amyotrophic lateral sclerosis","volume":"377","author":"Kiernan","year":"2011","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3109\/21678421.2015.1074704","article-title":"Non-self-sufficiency as a primary outcome measure in ALS trials","volume":"17","author":"Marin","year":"2015","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15580","DOI":"10.1038\/s41598-020-72578-3","article-title":"The 6-min walk test as a new outcome measure in Amyotrophic lateral sclerosis","volume":"10","author":"Russo","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"558","DOI":"10.3109\/17482961003792958","article-title":"The 10-metre gait speed as a functional biomarker in amyotrophic lateral sclerosis","volume":"11","author":"Inam","year":"2010","journal-title":"Amyotroph. Lateral. Scler."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.brainres.2009.11.051","article-title":"Moderate exercise delays the motor performance decline in a transgenic model of ALS","volume":"1313","author":"Carreras","year":"2010","journal-title":"Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0022-510X(01)00610-4","article-title":"The value of muscle exercise in patients with amyotrophic lateral sclerosis","volume":"191","author":"Drory","year":"2001","journal-title":"J. Neurol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.2169\/internalmedicine.8030-21","article-title":"Effects of Long-term Hybrid Assistive Limb Use on Gait in Patients with Amyotrophic Lateral Sclerosis","volume":"61","author":"Morioka","year":"2022","journal-title":"Intern. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"189","DOI":"10.4103\/1673-5374.244782","article-title":"Amyotrophic lateral sclerosis as a synaptopathy","volume":"14","author":"Fogarty","year":"2019","journal-title":"Neural Regen. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"660693","DOI":"10.3389\/fncel.2021.660693","article-title":"Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion","volume":"15","author":"Nishimura","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3389\/fnmol.2016.00160","article-title":"Neuromuscular Junction Impairment in Amyotrophic Lateral Sclerosis: Reassessing the Role of Acetylcholinesterase","volume":"9","author":"Campanari","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1523\/JNEUROSCI.20-07-02534.2000","article-title":"Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases","volume":"20","author":"Frey","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jchemneu.2016.03.003","article-title":"Axonal degeneration, distal collateral branching and neuromuscular junction architecture alterations occur prior to symptom onset in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis","volume":"76","author":"Clark","year":"2016","journal-title":"J. Chem. Neuroanat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1002\/acn3.179","article-title":"Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients","volume":"2","author":"Bruneteau","year":"2015","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.expneurol.2003.10.004","article-title":"Amyotrophic lateral sclerosis is a distal axonopathy: Evidence in mice and man","volume":"185","author":"Fischer","year":"2004","journal-title":"Exp. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Iyer, S.R., Shah, S.B., and Lovering, R.M. (2021). The Neuromuscular Junction: Roles in Aging and Neuromuscular Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158058"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/S1474-4422(17)30408-8","article-title":"Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders","volume":"17","author":"Augustin","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1093\/advances\/nmaa073","article-title":"To Keto or Not to Keto? A Systematic Review of Randomized Controlled Trials Assessing the Effects of Ketogenic Therapy on Alzheimer Disease","volume":"11","author":"Grammatikopoulou","year":"2020","journal-title":"Adv. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.maturitas.2022.06.001","article-title":"Ketogenic therapy for Parkinson\u2019s disease: A systematic review and synthesis without meta-analysis of animal and human trials","volume":"163","author":"Grammatikopoulou","year":"2022","journal-title":"Maturitas"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1080\/21678421.2021.1990346","article-title":"ALSUntangled #63: Ketogenic diets","volume":"24","author":"Bedlack","year":"2023","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhao, W., Varghese, M., Vempati, P., Dzhun, A., Cheng, A., Wang, J., Lange, D., Bilski, A., Faravelli, I., and Pasinetti, G.M. (2012). Caprylic triglyceride as a novel therapeutic approach to effectively improve the performance and attenuate the symptoms due to the motor neuron loss in ALS disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049191"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1242\/dmm.008029","article-title":"The antiepileptic drug valproic acid and other medium-chain fatty acids acutely reduce phosphoinositide levels independently of inositol in Dictyostelium","volume":"5","author":"Chang","year":"2012","journal-title":"Dis. Models Mech."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.neuropharm.2012.11.004","article-title":"Seizure control by ketogenic diet-associated medium chain fatty acids","volume":"69","author":"Chang","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1093\/brain\/awv325","article-title":"Seizure control by decanoic acid through direct AMPA receptor inhibition","volume":"139","author":"Chang","year":"2016","journal-title":"Brain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS","volume":"72","author":"Mackenzie","year":"2011","journal-title":"Neuron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1212\/WNL.0000000000003067","article-title":"Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population","volume":"87","author":"Umoh","year":"2016","journal-title":"Neurology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1136\/jnnp-2020-325377","article-title":"Unravelling the clinical spectrum and the role of repeat length in","volume":"92","author":"Jackson","year":"2021","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3389\/fnmol.2017.00035","article-title":"The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD","volume":"10","author":"Freibaum","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/nature14974","article-title":"GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport","volume":"525","author":"Freibaum","year":"2015","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1126\/science.1256800","article-title":"C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins","volume":"345","author":"Mizielinska","year":"2014","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.neuron.2014.12.010","article-title":"Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS\/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death","volume":"84","author":"Wen","year":"2014","journal-title":"Neuron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.cell.2016.10.002","article-title":"C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles","volume":"167","author":"Lee","year":"2016","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.1093\/hmg\/ddx304","article-title":"Homeostatic plasticity can be induced and expressed to restore synaptic strength at neuromuscular junctions undergoing ALS-related degeneration","volume":"26","author":"Perry","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1242\/dev.118.2.401","article-title":"Targeted gene expression as a means of altering cell fates and generating dominant phenotypes","volume":"118","author":"Brand","year":"1993","journal-title":"Development"},{"key":"ref_37","first-page":"2445","article-title":"Myostatin-like proteins regulate synaptic function and neuronal morphology","volume":"144","author":"Augustin","year":"2017","journal-title":"Development"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Robinson, S.W., Bourgognon, J.M., Spiers, J.G., Breda, C., Campesan, S., Butcher, A., Mallucci, G.R., Dinsdale, D., Morone, N., and Mistry, R. (2018). Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2003611"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1124061","DOI":"10.3389\/fnsyn.2023.1124061","article-title":"Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogaster","volume":"15","author":"Stone","year":"2023","journal-title":"Front. Synaptic Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/BF00215114","article-title":"Improved stability of Drosophila larval neuromuscular preparations in haemolymph-like physiological solutions","volume":"175","author":"Stewart","year":"1994","journal-title":"J. Comp. Physiol. A"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Ebshiana, A.A., Snowden, S.G., Thambisetty, M., Parsons, R., Hye, A., and Legido-Quigley, C. (2015). Metabolomic method: UPLC-q-ToF polar and non-polar metabolites in the healthy rat cerebellum using an in-vial dual extraction. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122883"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Fernandes, H.J.R., Kent, J.P., Bruntraeger, M., Bassett, A.R., Koulman, A., Metzakopian, E., and Snowden, S.G. (2023). Mitochondrial and Endoplasmic Reticulum Stress Trigger Triglyceride Accumulation in Models of Parkinson\u2019s Disease Independent of Mutations in MAPT. Metabolites, 13.","DOI":"10.3390\/metabo13010112"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1038\/nbt.2377","article-title":"A cross-platform toolkit for mass spectrometry and proteomics","volume":"30","author":"Chambers","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1021\/ac202450g","article-title":"CAMERA: An integrated strategy for compound spectra extraction and annotation of liquid chromatography\/mass spectrometry data sets","volume":"84","author":"Kuhl","year":"2012","journal-title":"Anal. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.gep.2009.01.002","article-title":"Genomic mapping and expression patterns of C380, OK6 and D42 enhancer trap lines in the larval nervous system of Drosophila","volume":"9","author":"Sanyal","year":"2009","journal-title":"Gene Expr. Patterns"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"17253","DOI":"10.1523\/JNEUROSCI.3334-13.2013","article-title":"Spontaneous and evoked release are independently regulated at individual active zones","volume":"33","author":"Melom","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.cbpa.2009.04.626","article-title":"From action potential to contraction: Neural control and excitation-contraction coupling in larval muscles of Drosophila","volume":"154","author":"Peron","year":"2009","journal-title":"Comp. Biochem. Physiol. A Mol. Integr. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.1523\/JNEUROSCI.19-08-03023.1999","article-title":"Glutamate receptor expression regulates quantal size and quantal content at the Drosophila neuromuscular junction","volume":"19","author":"DiAntonio","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.conb.2007.01.001","article-title":"Synaptic development: Insights from Drosophila","volume":"17","author":"Collins","year":"2006","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0074-7742(06)75001-2","article-title":"Introduction on the use of the Drosophila embryonic\/larval neuromuscular junction as a model system to study synapse development and function, and a brief summary of pathfinding and target recognition","volume":"75","author":"Budnik","year":"2006","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7362","DOI":"10.1523\/JNEUROSCI.22-17-07362.2002","article-title":"The postsynaptic glutamate receptor subunit DGluR-IIA mediates long-term plasticity in Drosophila","volume":"22","author":"Sigrist","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1124\/jpet.114.218768","article-title":"Seizure control by derivatives of medium chain fatty acids associated with the ketogenic diet show novel branching-point structure for enhanced potency","volume":"352","author":"Chang","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"145","DOI":"10.5941\/MYCO.2012.40.2.145","article-title":"Nonanoic Acid, an Antifungal Compound from Hibiscus syriacus Ggoma","volume":"40","author":"Jang","year":"2012","journal-title":"Mycobiology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.intimp.2018.10.022","article-title":"Caprylic acid and nonanoic acid upregulate endogenous host defense peptides to enhance intestinal epithelial immunological barrier function via histone deacetylase inhibition","volume":"65","author":"Wang","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"228S","DOI":"10.1177\/1091581811428980","article-title":"Final report of the Cosmetic Ingredient Review Expert Panel on the safety assessment of pelargonic acid (nonanoic acid) and nonanoate esters","volume":"30","author":"Johnson","year":"2011","journal-title":"Int. J. Toxicol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.neuroscience.2007.03.001","article-title":"Induction of neurite outgrowth in PC12 cells by the medium-chain fatty acid octanoic acid","volume":"146","author":"Kamata","year":"2007","journal-title":"Neuroscience"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"90","DOI":"10.3389\/fncel.2020.00090","article-title":"Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases","volume":"14","author":"Gomes","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e00155-18","DOI":"10.1128\/MCB.00155-18","article-title":"The C9ORF72 Gene, Implicated in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia, Encodes a Protein That Functions in Control of Endothelin and Glutamate Signaling","volume":"38","author":"Fomin","year":"2018","journal-title":"Mol. Cell. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.neuropharm.2018.12.013","article-title":"Ketone body modulation of ligand-gated ion channels","volume":"148","author":"Pflanz","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_60","unstructured":"Stanback, A.E. (2019). The Effects of a Ketone Body on Synaptic Transmission. Theses Diss.-Biol., 57."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/S1089-3261(05)70143-4","article-title":"Urea cycle disorders","volume":"4","author":"Burton","year":"2000","journal-title":"Clin. Liver Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S0301-0082(02)00019-9","article-title":"Neurobiology of ammonia","volume":"67","author":"Felipo","year":"2002","journal-title":"Prog. Neurobiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"100510","DOI":"10.1016\/j.jhepr.2022.100510","article-title":"Hyperammonaemia induces mitochondrial dysfunction and neuronal cell death","volume":"4","author":"Angelova","year":"2022","journal-title":"JHEP Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"119","DOI":"10.12688\/f1000research.6364.1","article-title":"A(a)LS: Ammonia-induced amyotrophic lateral sclerosis","volume":"4","author":"Parekh","year":"2015","journal-title":"F1000Research"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1111\/j.1600-0404.1982.tb03148.x","article-title":"Free amino acid concentrations in spinal tissue from patients dying of motor neuron disease","volume":"66","author":"Patten","year":"1982","journal-title":"Acta Neurol. Scand."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.bbadis.2013.10.004","article-title":"Amino acids as biomarkers in the SOD1(G93A) mouse model of ALS","volume":"1842","author":"Bame","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.2147\/PPA.S136754","article-title":"Profile of sodium phenylbutyrate granules for the treatment of urea-cycle disorders: Patient perspectives","volume":"11","author":"Llarena","year":"2017","journal-title":"Patient Prefer. Adherence"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1056\/NEJMoa1916945","article-title":"Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis","volume":"383","author":"Paganoni","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1111\/j.1471-4159.2005.03077.x","article-title":"Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice","volume":"93","author":"Ryu","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1039\/C7MO00114B","article-title":"Proteomic profile of 4-PBA treated human neuronal cells during ER stress","volume":"14","author":"Kaur","year":"2018","journal-title":"Mol. Omics"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1023\/B:NEUR.0000020612.87729.98","article-title":"The role of nitric oxide signaling in the formation of the neuromuscular junction","volume":"32","author":"Godfrey","year":"2003","journal-title":"J. Neurocytol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1089\/ars.2008.2234","article-title":"Nitric oxide in health and disease of the nervous system","volume":"11","author":"Knott","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5681036","DOI":"10.1155\/2016\/5681036","article-title":"Nitric Oxide-Mediated Posttranslational Modifications: Impacts at the Synapse","volume":"2016","author":"Bradley","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1046\/j.1471-4159.1998.70041541.x","article-title":"Nitric oxide causes glutamate release from brain synaptosomes","volume":"70","author":"McNaught","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6480","DOI":"10.1523\/JNEUROSCI.21-17-06480.2001","article-title":"Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity","volume":"21","author":"Brown","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"831","DOI":"10.2174\/1567205018666211022164025","article-title":"Functional Roles of Neuronal Nitric Oxide Synthase in Neurodegenerative Diseases and Mood Disorders","volume":"18","author":"Poon","year":"2021","journal-title":"Curr. Alzheimer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s12640-012-9322-y","article-title":"Nitric oxide-mediated oxidative damage and the progressive demise of motor neurons in ALS","volume":"22","author":"Drechsel","year":"2012","journal-title":"Neurotox. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/ana.410420416","article-title":"Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis","volume":"42","author":"Beal","year":"1997","journal-title":"Ann. Neurol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/ana.410420309","article-title":"Increased 3-nitrotyrosine and oxidative damage in mice with a human copper\/zinc superoxide dismutase mutation","volume":"42","author":"Ferrante","year":"1997","journal-title":"Ann. Neurol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.phrs.2015.11.020","article-title":"Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model","volume":"103","author":"Sestito","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0306-4522(02)00238-5","article-title":"L-citrulline immunostaining identifies nitric oxide production sites within neurons","volume":"114","author":"Martinelli","year":"2002","journal-title":"Neuroscience"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1007\/s12035-020-02143-6","article-title":"L-Citrulline Level and Transporter Activity Are Altered in Experimental Models of Amyotrophic Lateral Sclerosis","volume":"58","author":"Gyawali","year":"2021","journal-title":"Mol. 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