{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:56:06Z","timestamp":1790873766243,"version":"4.1.0"},"reference-count":124,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education, Taiwan under the Higher Education Sprout Project","award":["DP2-TMU-112-N-04"],"award-info":[{"award-number":["DP2-TMU-112-N-04"]}]},{"name":"Ministry of Education, Taiwan under the Higher Education Sprout Project","award":["MOST 110-2811-B-038-535"],"award-info":[{"award-number":["MOST 110-2811-B-038-535"]}]},{"name":"Ministry of Education, Taiwan under the Higher Education Sprout Project","award":["NSTC 112-2410-H-038-012-MY2"],"award-info":[{"award-number":["NSTC 112-2410-H-038-012-MY2"]}]},{"name":"Ministry of Education, Taiwan under the Higher Education Sprout Project","award":["NSTC 113-2321-B-038-007"],"award-info":[{"award-number":["NSTC 113-2321-B-038-007"]}]},{"name":"Ministry of Education, Taiwan under the Higher Education Sprout Project","award":["NSTC 114-2314-B-038-061"],"award-info":[{"award-number":["NSTC 114-2314-B-038-061"]}]},{"name":"National Science and Technology Council, Taiwan","award":["DP2-TMU-112-N-04"],"award-info":[{"award-number":["DP2-TMU-112-N-04"]}]},{"name":"National Science and Technology Council, Taiwan","award":["MOST 110-2811-B-038-535"],"award-info":[{"award-number":["MOST 110-2811-B-038-535"]}]},{"name":"National Science and Technology Council, Taiwan","award":["NSTC 112-2410-H-038-012-MY2"],"award-info":[{"award-number":["NSTC 112-2410-H-038-012-MY2"]}]},{"name":"National Science and Technology Council, Taiwan","award":["NSTC 113-2321-B-038-007"],"award-info":[{"award-number":["NSTC 113-2321-B-038-007"]}]},{"name":"National Science and Technology Council, Taiwan","award":["NSTC 114-2314-B-038-061"],"award-info":[{"award-number":["NSTC 114-2314-B-038-061"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in motor symptoms such as bradykinesia, tremor, rigidity, and postural instability, as well as a wide variety of non-motor manifestations. Branched-chain amino acids (BCAAs)\u2014leucine, isoleucine, and valine\u2014are essential nutrients involved in neurotransmitter synthesis, energy metabolism, and cellular signaling. Emerging evidence suggests that BCAA metabolism is intricately linked to the pathophysiology of PD. Dysregulation of BCAA levels has been associated with energy metabolism, mitochondrial dysfunction, oxidative stress, neuroinflammation, and altered neurotransmission. Furthermore, the branched-chain ketoacid dehydrogenase kinase (BCKDK), a key regulator of BCAA catabolism, has been implicated in PD through its role in modulating neuronal energetics and redox homeostasis. In this review, we synthesize current molecular, genetic, microbiome, and clinical evidence on BCAA dysregulation in PD to provide an integrative perspective on the BCAA\u2013PD axis and highlight directions for future translational research. We explored the dualistic role of BCAAs as both potential neuroprotective agents and metabolic stressors, and critically examined the therapeutic prospects and limitations of BCAA supplementation and BCKDK targeting.<\/jats:p>","DOI":"10.3390\/ijms26146992","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T09:33:53Z","timestamp":1753090433000},"page":"6992","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Branched-Chain Amino Acids in Parkinson\u2019s Disease: Molecular Mechanisms and Therapeutic Potential"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7547-4620","authenticated-orcid":false,"given":"Hui-Yu","family":"Huang","sequence":"first","affiliation":[{"name":"Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Research Center for Digestive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan"},{"name":"Nutrition Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan"},{"name":"Neuroscience Research Center, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3866-1117","authenticated-orcid":false,"given":"Shu-Ping","family":"Tsao","sequence":"additional","affiliation":[{"name":"Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Nutrition Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8182-6901","authenticated-orcid":false,"given":"Tu-Hsueh","family":"Yeh","sequence":"additional","affiliation":[{"name":"Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Neuroscience Research Center, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Neurology, Taipei Medical University Hospital, Taipei 11031, Taiwan"},{"name":"Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"International Master\/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s disease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e080952","DOI":"10.1136\/bmj-2024-080952","article-title":"Projections for prevalence of Parkinson\u2019s disease and its driving factors in 195 countries and territories to 2050: Modelling study of Global Burden of Disease Study 2021","volume":"388","author":"Su","year":"2025","journal-title":"BMJ"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"04160","DOI":"10.7189\/jogh.13.04160","article-title":"Global, regional, and national burden of neurological disorders in 204 countries and territories worldwide","volume":"13","author":"Huang","year":"2023","journal-title":"J. Glob. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/S1474-4422(19)30320-5","article-title":"Identification of novel risk loci, causal insights, and heritable risk for Parkinson\u2019s disease: A meta-analysis of genome-wide association studies","volume":"18","author":"Nalls","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S1474-4422(19)30287-X","article-title":"The genetic architecture of Parkinson\u2019s disease","volume":"19","author":"Blauwendraat","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nrendo.2014.171","article-title":"Branched-chain amino acids in metabolic signalling and insulin resistance","volume":"10","author":"Lynch","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s11064-016-2057-z","article-title":"Interactions in the Metabolism of Glutamate and the Branched-Chain Amino Acids and Ketoacids in the CNS","volume":"42","author":"Yudkoff","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zaragoza, R. (2020). Transport of Amino Acids Across the Blood-Brain Barrier. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00973"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Du, C., Liu, W.J., Yang, J., Zhao, S.S., and Liu, H.X. (2022). The Role of Branched-Chain Amino Acids and Branched-Chain alpha-Keto Acid Dehydrogenase Kinase in Metabolic Disorders. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.932670"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/d41573-021-00107-6","article-title":"BCKDK: An emerging kinase target for metabolic diseases and cancer","volume":"20","author":"East","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1093\/brain\/awad010","article-title":"BCKDK deficiency: A treatable neurodevelopmental disease amenable to newborn screening","volume":"146","author":"Tangeraas","year":"2023","journal-title":"Brain"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s40478-024-01915-8","article-title":"BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson\u2019s disease","volume":"12","author":"Jishi","year":"2024","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1007\/s10072-019-04143-4","article-title":"Quantitative metabolomics of saliva using proton NMR spectroscopy in patients with Parkinson\u2019s disease and healthy controls","volume":"41","author":"Kumari","year":"2020","journal-title":"Neurol. Sci."},{"key":"ref_14","first-page":"549","article-title":"Metabolite and peptide levels in plasma and CSF differentiating healthy controls from patients with newly diagnosed Parkinson\u2019s disease","volume":"4","author":"Trupp","year":"2014","journal-title":"J. Park. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1039\/C5MB00711A","article-title":"Multi-platform mass spectrometry analysis of the CSF and plasma metabolomes of rigorously matched amyotrophic lateral sclerosis, Parkinson\u2019s disease and control subjects","volume":"12","author":"Wuolikainen","year":"2016","journal-title":"Mol. Biosyst."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Havelund, J.F., Heegaard, N.H.H., F\u00e6rgeman, N.J.K., and Gramsbergen, J.B. (2017). Biomarker Research in Parkinson\u2019s Disease Using Metabolite Profiling. Metabolites, 7.","DOI":"10.3390\/metabo7030042"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"207S","DOI":"10.1093\/jn\/136.1.207S","article-title":"Branched-chain amino acids: Enzyme and substrate regulation","volume":"136","author":"Brosnan","year":"2006","journal-title":"J. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00726-009-0269-0","article-title":"Amino acids: Metabolism, functions, and nutrition","volume":"37","author":"Wu","year":"2009","journal-title":"Amino Acids"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Monirujjaman, M., and Ferdouse, A. (2014). Metabolic and Physiological Roles of Branched-Chain Amino Acids. Adv. Mol. Biol., 2014.","DOI":"10.1155\/2014\/364976"},{"key":"ref_20","first-page":"103","article-title":"Branched-Chain Amino Acids","volume":"159","author":"Yamamoto","year":"2017","journal-title":"Adv. Biochem. Eng. Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1007\/s00726-017-2412-7","article-title":"Enzymes involved in branched-chain amino acid metabolism in humans","volume":"49","year":"2017","journal-title":"Amino Acids"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Dimou, A., Tsimihodimos, V., and Bairaktari, E. (2022). The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain alpha-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23074022"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12970-017-0184-9","article-title":"Branched-chain amino acids and muscle protein synthesis in humans: Myth or reality?","volume":"14","author":"Wolfe","year":"2017","journal-title":"J. Int. Soc. Sports Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.bbrc.2003.11.023","article-title":"Pharmacological activities of branched-chain amino acids: Specificity of tissue and signal transduction","volume":"313","author":"Nishitani","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e003330","DOI":"10.1161\/CIRCGEN.121.003330","article-title":"Association of Plasma Branched-Chain Amino Acid With Biomarkers of Inflammation and Lipid Metabolism in Women","volume":"14","author":"Hamaya","year":"2021","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8160545","DOI":"10.1155\/2016\/8160545","article-title":"Using Metabolomic Profiles as Biomarkers for Insulin Resistance in Childhood Obesity: A Systematic Review","volume":"2016","author":"Zhao","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"38","DOI":"10.4239\/wjd.v3.i3.38","article-title":"Leucine signaling in the pathogenesis of type 2 diabetes and obesity","volume":"3","author":"Melnik","year":"2012","journal-title":"World J. Diabetes"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1007\/s00726-015-1985-2","article-title":"Dietary L-leucine supplementation enhances intestinal development in suckling piglets","volume":"47","author":"Sun","year":"2015","journal-title":"Amino Acids"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhao, J., Zhao, Y., Liu, H., Cao, Q., Feng, L., Zhang, Z., Jiang, W., Wu, P., Liu, Y., and Luo, W. (2023). Dietary Leucine Improves Fish Intestinal Barrier Function by Increasing Humoral Immunity, Antioxidant Capacity, and Tight Junction. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054716"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.aninu.2015.11.005","article-title":"Effects of dietary leucine supplementation on the gene expression of mammalian target of rapamycin signaling pathway and intestinal development of broilers","volume":"1","author":"Chang","year":"2015","journal-title":"Anim. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1093\/hmg\/ddu123","article-title":"Branched-chain amino acid metabolism: From rare Mendelian diseases to more common disorders","volume":"23","author":"Burrage","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Nie, C., He, T., Zhang, W., Zhang, G., and Ma, X. (2018). Branched Chain Amino Acids: Beyond Nutrition Metabolism. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19040954"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/s12276-022-00775-3","article-title":"BCAT1 promotes osteoclast maturation by regulating branched-chain amino acid metabolism","volume":"54","author":"Go","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1097\/00000658-198403000-00007","article-title":"Branched chain metabolic support. A prospective, randomized, double-blind trial in surgical stress","volume":"199","author":"Cerra","year":"1984","journal-title":"Ann. Surg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1097\/00003246-199703000-00008","article-title":"Parenteral administration of different amounts of branch-chain amino acids in septic patients: Clinical and metabolic aspects","volume":"25","author":"Planas","year":"1997","journal-title":"Crit. Care Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"288S","DOI":"10.1093\/jn\/136.1.288S","article-title":"Branched-chain amino acids and immunity","volume":"136","author":"Calder","year":"2006","journal-title":"J. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1539S","DOI":"10.1093\/jn\/135.6.1539S","article-title":"Branched-chain amino acids and brain function","volume":"135","author":"Fernstrom","year":"2005","journal-title":"J. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S0899-9007(02)00753-0","article-title":"Branched-chain amino acid supplementation and the immune response of long-distance athletes","volume":"18","author":"Bassit","year":"2002","journal-title":"Nutrition"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s00726-012-1330-y","article-title":"Large neutral amino acids: Dietary effects on brain neurochemistry and function","volume":"45","author":"Fernstrom","year":"2013","journal-title":"Amino Acids"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/sj.npp.1300835","article-title":"Effect of acute tyrosine depletion in using a branched chain amino-acid mixture on dopamine neurotransmission in the rat brain","volume":"31","author":"Oldenzeil","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"E405","DOI":"10.1152\/ajpendo.00373.2012","article-title":"Branched-chain amino acids alter neurobehavioral function in rats","volume":"304","author":"Coppola","year":"2013","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1007\/s12640-009-9115-0","article-title":"Branched-chain amino acids induce neurotoxicity in rat cortical cultures","volume":"17","author":"Contrusciere","year":"2010","journal-title":"Neurotox. Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Wang, J., Wang, F., Mai, D., and Qu, S. (2020). Molecular Mechanisms of Glutamate Toxicity in Parkinson\u2019s Disease. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.585584"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s10522-020-09860-4","article-title":"Alzheimer\u2019s disease: Targeting the glutamatergic system","volume":"21","author":"Conway","year":"2020","journal-title":"Biogerontology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.bbadis.2013.02.001","article-title":"Branched-chain amino acids influence the immune properties of microglial cells and their responsiveness to pro-inflammatory signals","volume":"1832","author":"Vissicchio","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.freeradbiomed.2017.01.009","article-title":"High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation","volume":"104","author":"Zhenyukh","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, H., Ye, D., Xie, W., Hua, F., Yang, Y., Wu, J., Gu, A., Ren, Y., and Mao, K. (2018). Defect of branched-chain amino acid metabolism promotes the development of Alzheimer\u2019s disease by targeting the mTOR signaling. Biosci. Rep., 38.","DOI":"10.1042\/BSR20180127"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/S1474-4422(20)30231-3","article-title":"Brain insulin resistance in Alzheimer\u2019s disease and related disorders: Mechanisms and therapeutic approaches","volume":"19","author":"Kellar","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"847","DOI":"10.3233\/JAD-221147","article-title":"Insulin Resistance and Impaired Branched-Chain Amino Acid Metabolism in Alzheimer\u2019s Disease","volume":"93","author":"Liu","year":"2023","journal-title":"J. Alzheimers Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1002\/mds.29298","article-title":"Type 2 Diabetes and Parkinson\u2019s Disease: A Focused Review of Current Concepts","volume":"38","author":"Cullinane","year":"2023","journal-title":"Mov. Disord."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ye, Z., Wang, S., Zhang, C., and Zhao, Y. (2020). Coordinated Modulation of Energy Metabolism and Inflammation by Branched-Chain Amino Acids and Fatty Acids. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00617"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1038\/s41419-023-06135-x","article-title":"PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons","volume":"14","author":"Li","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"931","DOI":"10.3233\/JAD-180879","article-title":"Novel Blood Biomarkers that Correlate with Cognitive Performance and Hippocampal Volumetry: Potential for Early Diagnosis of Alzheimer\u2019s Disease","volume":"67","author":"Hudd","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Larsson, S.C., and Markus, H.S. (2017). Branched-chain amino acids and Alzheimer\u2019s disease: A Mendelian randomization analysis. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-12931-1"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/BF02252924","article-title":"Amino acid concentrations in cerebrospinal fluid and plasma in Alzheimer\u2019s disease and healthy control subjects","volume":"2","author":"Basun","year":"1990","journal-title":"J. Neural Transm. Park. Dis. Dement. Sect."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jpba.2014.10.010","article-title":"Metabolite profiling for the identification of altered metabolic pathways in Alzheimer\u2019s disease","volume":"107","year":"2015","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.jalz.2017.01.020","article-title":"Metabolic network failures in Alzheimer\u2019s disease: A biochemical road map","volume":"13","author":"Toledo","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Siddik, M.A.B., Mullins, C.A., Kramer, A., Shah, H., Gannaban, R.B., Zabet-Moghaddam, M., Huebinger, R.M., Hegde, V.K., MohanKumar, S.M.J., and MohanKumar, P.S. (2022). Branched-Chain Amino Acids Are Linked with Alzheimer\u2019s Disease-Related Pathology and Cognitive Deficits. Cells, 11.","DOI":"10.3390\/cells11213523"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.cca.2018.02.022","article-title":"Serum metabolomics study in a group of Parkinson\u2019s disease patients from northern India","volume":"480","author":"Gupta","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Figura, M., Kusmierska, K., Bucior, E., Szlufik, S., Koziorowski, D., Jamrozik, Z., and Janik, P. (2018). Serum amino acid profile in patients with Parkinson\u2019s disease. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191670"},{"key":"ref_61","first-page":"1129","article-title":"The Associations Among Gut Microbiota, Branched Chain Amino Acids, and Parkinson\u2019s Disease: Mendelian Randomization Study","volume":"14","author":"Yan","year":"2024","journal-title":"J. Park. Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e00561-20","DOI":"10.1128\/mSystems.00561-20","article-title":"Gut Microbiota and Metabolome Alterations Associated with Parkinson\u2019s Disease","volume":"5","author":"Vascellari","year":"2020","journal-title":"mSystems"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Chang, K.H., Lin, C.N., Chen, C.M., Lyu, R.K., Chu, C.C., Liao, M.F., Huang, C.C., Chang, H.S., Ro, L.S., and Kuo, H.C. (2021). Altered Metabolic Profiles of the Plasma of Patients with Amyotrophic Lateral Sclerosis. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121944"},{"key":"ref_64","first-page":"e2081","article-title":"Prediagnostic plasma branched-chain amino acids and the risk of amyotrophic lateral sclerosis","volume":"92","author":"Bjornevik","year":"2019","journal-title":"Neurology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"105187","DOI":"10.1016\/j.micpath.2021.105187","article-title":"Alterations of gut microbiota and metabolome with Parkinson\u2019s disease","volume":"160","author":"Yan","year":"2021","journal-title":"Microb. Pathog."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/s41531-022-00312-z","article-title":"Plasma branched-chain and aromatic amino acids correlate with the gut microbiota and severity of Parkinson\u2019s disease","volume":"8","author":"Zhang","year":"2022","journal-title":"npj Park. Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1212\/WNL.47.5.1220","article-title":"A controlled trial of amino acid therapy in amyotrophic lateral sclerosis: I. Clinical, functional, and maximum isometric torque data","volume":"47","author":"Tandan","year":"1996","journal-title":"Neurology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00726-021-03117-1","article-title":"Longitudinal metabolomics profiling of serum amino acids in rotenone-induced Parkinson\u2019s mouse model","volume":"54","author":"Yan","year":"2022","journal-title":"Amino Acids"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Fu, Y., Wang, Y., Ren, H., Guo, X., and Han, L. (2024). Branched-chain amino acids and the risks of dementia, Alzheimer\u2019s disease, and Parkinson\u2019s disease. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1369493"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Luan, H., Liu, L.F., Tang, Z., Zhang, M., Chua, K.K., Song, J.X., Mok, V.C., Li, M., and Cai, Z. (2015). Comprehensive urinary metabolomic profiling and identification of potential noninvasive marker for idiopathic Parkinson\u2019s disease. Sci. Rep., 5.","DOI":"10.1038\/srep13888"},{"key":"ref_71","first-page":"606","article-title":"Assessment of the Relationship Between Amino Acid Status and Parkinson\u2019s Disease: A Comprehensive Review and Meta-analysis","volume":"52","author":"Akdas","year":"2024","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1002\/mds.30054","article-title":"Gut Microbial Metabolites and Future Risk of Parkinson\u2019s Disease: A Metabolome-Wide Association Study","volume":"40","author":"Zhao","year":"2024","journal-title":"Mov. Disord."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s40035-023-00392-8","article-title":"Parkinson\u2019s disease and gut microbiota: From clinical to mechanistic and therapeutic studies","volume":"12","author":"Zhang","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/s41582-022-00681-2","article-title":"The microbiome-gut-brain axis in Parkinson disease\u2014From basic research to the clinic","volume":"18","author":"Tan","year":"2022","journal-title":"Nat. Rev. Neurol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"106101","DOI":"10.1016\/j.parkreldis.2024.106101","article-title":"Brain-first vs. body-first Parkinson\u2019s disease: An update on recent evidence","volume":"122","author":"Horsager","year":"2024","journal-title":"Park. Relat. Disord."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"5849","DOI":"10.1021\/acs.biochem.7b00849","article-title":"Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability","volume":"56","author":"Blanchard","year":"2017","journal-title":"Biochemistry"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Al Bander, Z., Nitert, M.D., Mousa, A., and Naderpoor, N. (2020). The Gut Microbiota and Inflammation: An Overview. Int. J. Environ. Res. Public. Health, 17.","DOI":"10.3390\/ijerph17207618"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"105840","DOI":"10.1016\/j.phrs.2021.105840","article-title":"The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders","volume":"172","author":"Socala","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e70099","DOI":"10.1111\/jcmm.70099","article-title":"Microbiota-gut-brain axis in health and neurological disease: Interactions between gut microbiota and the nervous system","volume":"28","author":"He","year":"2024","journal-title":"J. Cell. Mol. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1038\/s41396-023-01537-3","article-title":"Amino acid auxotrophies in human gut bacteria are linked to higher microbiome diversity and long-term stability","volume":"17","author":"Starke","year":"2023","journal-title":"ISME J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1128\/MMBR.00076-15","article-title":"Stress Physiology of Lactic Acid Bacteria","volume":"80","author":"Papadimitriou","year":"2016","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s41588-020-00763-1","article-title":"Large-scale association analyses identify host factors influencing human gut microbiome composition","volume":"53","author":"Kurilshikov","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Matheson, J.-A.T., and Holsinger, R.M.D. (2023). The Role of Fecal Microbiota Transplantation in the Treatment of Neurodegenerative Diseases: A Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021001"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/j.cmet.2018.04.015","article-title":"The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase","volume":"27","author":"White","year":"2018","journal-title":"Cell Metab."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Acevedo, A., Jones, A.E., Danna, B.T., Turner, R., Montales, K.P., Beninca, C., Reue, K., Shirihai, O.S., Stiles, L., and Wallace, M. (2024). The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis. J. Biol. Chem., 300.","DOI":"10.1016\/j.jbc.2024.105702"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e011625","DOI":"10.1161\/JAHA.118.011625","article-title":"Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure","volume":"8","author":"Chen","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ebiom.2017.05.001","article-title":"BCKDK of BCAA Catabolism Cross-talking With the MAPK Pathway Promotes Tumorigenesis of Colorectal Cancer","volume":"20","author":"Xue","year":"2017","journal-title":"EBioMedicine"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1038\/ng.3043","article-title":"Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson\u2019s disease","volume":"46","author":"Nalls","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1038\/ng.3955","article-title":"A meta-analysis of genome-wide association studies identifies 17 new Parkinson\u2019s disease risk loci","volume":"49","author":"Chang","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_90","first-page":"3489638","article-title":"Polymorphisms of ACMSD-TMEM163, MCCC1, and BCKDK-STX1B Are Not Associated with Parkinson\u2019s Disease in Taiwan","volume":"2019","author":"Chang","year":"2019","journal-title":"Park. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.neulet.2019.03.019","article-title":"Association of three candidate genetic variants in ACMSD\/TMEM163, GPNMB and BCKDK\/STX1B with sporadic Parkinson\u2019s disease in Han Chinese","volume":"703","author":"Wang","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_92","first-page":"101091","article-title":"Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency","volume":"39","author":"Ohl","year":"2024","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"eaau6323","DOI":"10.1126\/science.aau6323","article-title":"Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism","volume":"364","author":"Bess","year":"2019","journal-title":"Science"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Nam, G.E., Kim, S.M., Han, K., Kim, N.H., Chung, H.S., Kim, J.W., Han, B., Cho, S.J., Yu, J.H., and Park, Y.G. (2018). Metabolic syndrome and risk of Parkinson disease: A nationwide cohort study. PLoS Med., 15.","DOI":"10.1371\/journal.pmed.1002640"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.jns.2016.05.056","article-title":"Biochemical and clinical effects of Whey protein supplementation in Parkinson\u2019s disease: A pilot study","volume":"367","author":"Tosukhowong","year":"2016","journal-title":"J. Neurol. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"110766","DOI":"10.1016\/j.exger.2019.110766","article-title":"Circulating amino acid signature in older people with Parkinson\u2019s disease: A metabolic complement to the EXosomes in PArkiNson Disease (EXPAND) study","volume":"128","author":"Picca","year":"2019","journal-title":"Exp. Gerontol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41392-024-01743-1","article-title":"Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases","volume":"9","author":"Loh","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.clnu.2014.12.007","article-title":"Amino acid supplementation in l-dopa treated Parkinson\u2019s disease patients","volume":"34","author":"Cucca","year":"2015","journal-title":"Clin. Nutr."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"20230849","DOI":"10.1515\/med-2023-0849","article-title":"Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson\u2019s disease after dietary supplementation with branched-chain amino acids","volume":"18","author":"Mi","year":"2023","journal-title":"Open Med."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Chu, C., Yu, L., Li, Y., Guo, H., Zhai, Q., Chen, W., and Tian, F. (2023). Lactobacillus plantarum CCFM405 against Rotenone-Induced Parkinson\u2019s Disease Mice via Regulating Gut Microbiota and Branched-Chain Amino Acids Biosynthesis. Nutrients, 15.","DOI":"10.3390\/nu15071737"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.neuint.2018.03.001","article-title":"Current perspective of mitochondrial biology in Parkinson\u2019s disease","volume":"117","author":"Thomas","year":"2018","journal-title":"Neurochem. Int."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e2200109","DOI":"10.1002\/mnfr.202200109","article-title":"Branched-Chain Amino Acids and Mitochondrial Biogenesis: An Overview and Mechanistic Summary","volume":"66","author":"Hinkle","year":"2022","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1002\/mds.26069","article-title":"Gut microbiota are related to Parkinson\u2019s disease and clinical phenotype","volume":"30","author":"Scheperjans","year":"2015","journal-title":"Mov. Disord."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Feng, M., Zou, Z., Shou, P., Peng, W., Liu, M., and Li, X. (2024). Gut microbiota and Parkinson\u2019s disease: Potential links and the role of fecal microbiota transplantation. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1479343"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.parkreldis.2016.08.019","article-title":"Short chain fatty acids and gut microbiota differ between patients with Parkinson\u2019s disease and age-matched controls","volume":"32","author":"Unger","year":"2016","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1007\/s10517-017-3700-7","article-title":"Analysis of Gut Microbiota in Patients with Parkinson\u2019s Disease","volume":"162","author":"Petrov","year":"2017","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1002\/mds.26942","article-title":"Parkinson\u2019s disease and Parkinson\u2019s disease medications have distinct signatures of the gut microbiome","volume":"32","author":"Debelius","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1111\/ene.13398","article-title":"More than constipation - bowel symptoms in Parkinson\u2019s disease and their connection to gut microbiota","volume":"24","author":"Mertsalmi","year":"2017","journal-title":"Eur. J. Neurol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13073-017-0428-y","article-title":"Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naive Parkinson\u2019s disease patients","volume":"9","author":"Bedarf","year":"2017","journal-title":"Genome Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1007\/s11427-016-9001-4","article-title":"Structural changes of gut microbiota in Parkinson\u2019s disease and its correlation with clinical features","volume":"60","author":"Li","year":"2017","journal-title":"Sci. China Life Sci."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/mds.27105","article-title":"The nasal and gut microbiome in Parkinson\u2019s disease and idiopathic rapid eye movement sleep behavior disorder","volume":"33","author":"Pandey","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.bbi.2018.02.016","article-title":"Alteration of the fecal microbiota in Chinese patients with Parkinson\u2019s disease","volume":"70","author":"Qian","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.ebiom.2019.05.064","article-title":"Gut microbiota in Parkinson\u2019s disease: Temporal stability and relations to disease progression","volume":"44","author":"Aho","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1002\/mds.27581","article-title":"Unraveling gut microbiota in Parkinson\u2019s disease and atypical parkinsonism","volume":"34","author":"Barichella","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1002\/mds.28052","article-title":"Microbiota Composition and Metabolism Are Associated With Gut Function in Parkinson\u2019s Disease","volume":"35","author":"Cirstea","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Baldini, F., Hertel, J., Sandt, E., Thinnes, C.C., Neuberger-Castillo, L., Pavelka, L., Betsou, F., Kruger, R., Thiele, I., and Consortium, N.-P. (2020). Parkinson\u2019s disease-associated alterations of the gut microbiome predict disease-relevant changes in metabolic functions. BMC Biol., 18.","DOI":"10.1101\/691030"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1093\/brain\/awaa201","article-title":"Gut metagenomics-derived genes as potential biomarkers of Parkinson\u2019s disease","volume":"143","author":"Qian","year":"2020","journal-title":"Brain"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"108807","DOI":"10.1016\/j.celrep.2021.108807","article-title":"Systematic analysis of gut microbiome reveals the role of bacterial folate and homocysteine metabolism in Parkinson\u2019s disease","volume":"34","author":"Rosario","year":"2021","journal-title":"Cell Rep."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/ana.25982","article-title":"Gut Microbial Ecosystem in Parkinson Disease: New Clinicobiological Insights from Multi-Omics","volume":"89","author":"Tan","year":"2021","journal-title":"Ann. Neurol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"6958","DOI":"10.1038\/s41467-022-34667-x","article-title":"Metagenomics of Parkinson\u2019s disease implicates the gut microbiome in multiple disease mechanisms","volume":"13","author":"Wallen","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.3233\/JPD-223500","article-title":"Parkinson\u2019s Disease and the Gut Microbiome in Rural California","volume":"12","author":"Zhang","year":"2022","journal-title":"J. Parkinsons Dis."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/mds.29300","article-title":"Integrated Multi-Cohort Analysis of the Parkinson\u2019s Disease Gut Metagenome","volume":"38","author":"Boktor","year":"2023","journal-title":"Mov. Disord."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/s13760-023-02195-0","article-title":"Altered gut microbiota in patients with idiopathic Parkinson\u2019s disease: An age-sex matched case-control study","volume":"123","author":"Kayacan","year":"2023","journal-title":"Acta Neurol."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Nie, S., Wang, J., Deng, Y., Ye, Z., and Ge, Y. (2022). Inflammatory microbes and genes as potential biomarkers of Parkinson\u2019s disease. npj Biofilms Microbiomes, 8.","DOI":"10.1038\/s41522-022-00367-z"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6992\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:13:10Z","timestamp":1760033590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6992"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,21]]},"references-count":124,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26146992"],"URL":"https:\/\/doi.org\/10.3390\/ijms26146992","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,21]]}}}