{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T22:35:09Z","timestamp":1789770909222,"version":"4.0.1"},"reference-count":51,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T00:00:00Z","timestamp":1734739200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T00:00:00Z","timestamp":1734739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG065240"],"award-info":[{"award-number":["R01AG065240"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS115903"],"award-info":[{"award-number":["R01NS115903"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"DOI":"10.1186\/s40478-024-01915-8","type":"journal-article","created":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T02:51:26Z","timestamp":1734749486000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson\u2019s disease"],"prefix":"10.1186","volume":"12","author":[{"given":"Aya","family":"Jishi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rihua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Gunzler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,21]]},"reference":[{"key":"1915_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.13","author":"W Poewe","year":"2017","unstructured":"Poewe W et al (2017) Parkinson disease. Nat Rev Dis Primer. https:\/\/doi.org\/10.1038\/nrdp.2017.13","journal-title":"Nat Rev Dis Primer"},{"key":"1915_CR2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/114.5.2283","author":"JM Fearnley","year":"1991","unstructured":"Fearnley JM, Lees AJ (1991) Ageing and parkinson\u2019s disease: Substantia nigra regional selectivity. Brain. https:\/\/doi.org\/10.1093\/brain\/114.5.2283","journal-title":"Brain"},{"key":"1915_CR3","doi-asserted-by":"publisher","DOI":"10.4103\/0028-3886.226451","author":"DM Radhakrishnan","year":"2018","unstructured":"Radhakrishnan DM, Goyal V (2018) Parkinson\u2019s disease: A review. Neurol India. https:\/\/doi.org\/10.4103\/0028-3886.226451","journal-title":"Neurol India"},{"key":"1915_CR4","doi-asserted-by":"crossref","unstructured":"Tysnes OB, Storstein A (2017) Epidemiology of Parkinson\u2019s disease. J Neural Transm 124","DOI":"10.1007\/s00702-017-1686-y"},{"key":"1915_CR5","doi-asserted-by":"publisher","DOI":"10.2741\/s415","author":"JM Beitz","year":"2014","unstructured":"Beitz JM (2014) Parkinson\u2019s disease: A review. Front Biosci - Sch. https:\/\/doi.org\/10.2741\/s415","journal-title":"Front Biosci - Sch"},{"key":"1915_CR6","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009332","author":"C Perier","year":"2012","unstructured":"Perier C, Vila M (2012) Mitochondrial biology and Parkinson\u2019s disease. Cold Spring Harb Perspect Med. https:\/\/doi.org\/10.1101\/cshperspect.a009332","journal-title":"Cold Spring Harb Perspect Med"},{"key":"1915_CR7","doi-asserted-by":"publisher","first-page":"38","DOI":"10.3390\/biology8020038","volume":"8","author":"C Chen","year":"2019","unstructured":"Chen C, Turnbull DM, Reeve AK (2019) Mitochondrial dysfunction in Parkinson\u2019s disease\u2014cause or consequence? Biology 8:38","journal-title":"Biology"},{"key":"1915_CR8","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-018-0829-3","author":"JS Park","year":"2018","unstructured":"Park JS, Davis RL, Sue CM (2018) Mitochondrial Dysfunction in Parkinson\u2019s Disease: New Mechanistic Insights and Therapeutic Perspectives. Curr Neurol Neurosci Rep. https:\/\/doi.org\/10.1007\/s11910-018-0829-3","journal-title":"Curr Neurol Neurosci Rep"},{"key":"1915_CR9","doi-asserted-by":"publisher","first-page":"5371","DOI":"10.1172\/JCI70911","volume":"123","author":"X Guo","year":"2013","unstructured":"Guo X et al (2013) Inhibition of mitochondrial fragmentation diminishes Huntington\u2019s disease-associated neurodegeneration. J Clin Invest 123:5371\u20135388","journal-title":"J Clin Invest"},{"key":"1915_CR10","doi-asserted-by":"crossref","unstructured":"Santos D, Esteves AR, Silva DF, Janu\u00e1rio C, Cardoso SM (2015) The impact of mitochondrial fusion and fission modulation in sporadic Parkinson\u2019s disease. mol neurobiol 52","DOI":"10.1007\/s12035-014-8893-4"},{"key":"1915_CR11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M710012200","author":"L Devi","year":"2008","unstructured":"Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK (2008) Mitochondrial import and accumulation of \u03b1-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem. https:\/\/doi.org\/10.1074\/jbc.M710012200","journal-title":"J Biol Chem"},{"key":"1915_CR12","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Rodr\u00edguez P et al (2021) Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 599","DOI":"10.1038\/s41586-021-04059-0"},{"key":"1915_CR13","doi-asserted-by":"crossref","unstructured":"Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in parkinson\u2019s disease. J Park Dis 3","DOI":"10.3233\/JPD-130230"},{"key":"1915_CR14","doi-asserted-by":"crossref","unstructured":"Henderson MX, Trojanowski JQ, Lee VM (2019) Y. \u03b1-Synuclein pathology in Parkinson\u2019s disease and related \u03b1-synucleinopathies. Neurosci Lett 709","DOI":"10.1016\/j.neulet.2019.134316"},{"key":"1915_CR15","doi-asserted-by":"crossref","unstructured":"Calabresi P et al (2023) Alpha-synuclein in Parkinson\u2019s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis 14","DOI":"10.1038\/s41419-023-05672-9"},{"key":"1915_CR16","doi-asserted-by":"publisher","first-page":"388","DOI":"10.3389\/fnins.2018.00388","volume":"12","author":"M Vicario","year":"2018","unstructured":"Vicario M, Cieri D, Brini M, Cal\u00ec T (2018) The close encounter between alpha-synuclein and mitochondria. Front Neurosci 12:388","journal-title":"Front Neurosci"},{"key":"1915_CR17","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1126\/scitranslmed.aaf3634","volume":"8","author":"R Di Maio","year":"2016","unstructured":"Di Maio R et al (2016) \u03b1-synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson\u2019s disease. Sci Transl Med 8:78","journal-title":"Sci Transl Med"},{"key":"1915_CR18","doi-asserted-by":"crossref","unstructured":"Surmeier DJ, Obeso JA, Halliday GM (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18","DOI":"10.1038\/nrn.2016.178"},{"key":"1915_CR19","doi-asserted-by":"crossref","unstructured":"Choi ML et al (2022) Pathological structural conversion of \u03b1-synuclein at the mitochondria induces neuronal toxicity. Nat Neurosci 25","DOI":"10.1038\/s41593-022-01140-3"},{"key":"1915_CR20","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz350","author":"C Blauwendraat","year":"2020","unstructured":"Blauwendraat C et al (2020) Genetic modifiers of risk and age at onset in GBA associated Parkinson\u2019s disease and Lewy body dementia. Brain. https:\/\/doi.org\/10.1093\/brain\/awz350","journal-title":"Brain"},{"key":"1915_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5","author":"MA Nalls","year":"2019","unstructured":"Nalls MA et al (2019) Identification of novel risk loci, causal insights, and heritable risk for Parkinson\u2019s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. https:\/\/doi.org\/10.1016\/S1474-4422(19)30320-5","journal-title":"Lancet Neurol"},{"key":"1915_CR22","doi-asserted-by":"crossref","unstructured":"Chang D et al (2017) A meta-analysis of genome-wide association studies identifies 17 new Parkinson\u2019s disease risk loci. Nat Genet 49","DOI":"10.1038\/ng.3955"},{"key":"1915_CR23","doi-asserted-by":"crossref","unstructured":"Nalls MA et al (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson\u2019s disease. Nat Genet 46","DOI":"10.1038\/ng.3043"},{"key":"1915_CR24","unstructured":"Charlton M (2006) Branched-chain amino acids: Metabolism, physiological function, and application. J Nutr"},{"key":"1915_CR25","doi-asserted-by":"crossref","unstructured":"Wynn RM et al (2004) Molecular mechanism for regulation of the human mitochondrial branched-chain \u03b1-ketoacid dehydrogenase complex by phosphorylation. Structure 12","DOI":"10.2210\/pdb1u5b\/pdb"},{"key":"1915_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2016.01.016","author":"A Oyarzabal","year":"2016","unstructured":"Oyarzabal A et al (2016) Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism. Biochim Biophys Acta - Mol Basis Dis. https:\/\/doi.org\/10.1016\/j.bbadis.2016.01.016","journal-title":"Biochim Biophys Acta - Mol Basis Dis"},{"key":"1915_CR27","first-page":"101091","volume":"39","author":"L Ohl","year":"2024","unstructured":"Ohl L et al (2024) Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency. Mol Genet Metab Rep 39:101091","journal-title":"Mol Genet Metab Rep"},{"key":"1915_CR28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0070309","author":"M Iwasa","year":"2013","unstructured":"Iwasa M et al (2013) Branched-Chain Amino Acid Supplementation Reduces Oxidative Stress and Prolongs Survival in Rats with Advanced Liver Cirrhosis. PLoS ONE. https:\/\/doi.org\/10.1371\/journal.pone.0070309","journal-title":"PLoS ONE"},{"key":"1915_CR29","doi-asserted-by":"publisher","unstructured":"Mor DE et al (2020) Metformin rescues Parkinson\u2019s disease phenotypes caused by hyperactive mitochondria. Proc Natl Acad Sci. USA  https:\/\/doi.org\/10.1073\/pnas.2009838117","DOI":"10.1073\/pnas.2009838117"},{"key":"1915_CR30","doi-asserted-by":"crossref","unstructured":"Tangeraas T et al (2023) BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening. Brain 146","DOI":"10.1093\/brain\/awad010"},{"key":"1915_CR31","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/s41598-020-79990-9","volume":"11","author":"M Langmyhr","year":"2021","unstructured":"Langmyhr M et al (2021) Allele-specific expression of Parkinson\u2019s disease susceptibility genes in human brain. Sci Rep 11:504","journal-title":"Sci Rep"},{"key":"1915_CR32","doi-asserted-by":"crossref","unstructured":"Chen Z et al (2023) BCKDKrs14235 A allele is associated with milder motor impairment and altered network topology in Parkinson\u2019s disease","DOI":"10.1101\/2023.07.20.23292985"},{"key":"1915_CR33","doi-asserted-by":"crossref","unstructured":"Lee MK et al (2002) Human \u03b1-synuclein-harboring familial Parkinson\u2019s disease-linked Ala-53 \u2192 Thr mutation causes neurodegenerative disease with \u03b1-synuclein aggregation in transgenic mice. Proc Natl Acad Sci. 99, 8968\u20138973","DOI":"10.1073\/pnas.132197599"},{"key":"1915_CR34","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1007\/s00401-019-01993-2","volume":"137","author":"D Hu","year":"2019","unstructured":"Hu D et al (2019) Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity. Acta Neuropathol (Berl) 137:939\u2013960","journal-title":"Acta Neuropathol (Berl)"},{"key":"1915_CR35","doi-asserted-by":"publisher","first-page":"e1867","DOI":"10.1371\/journal.pone.0001867","volume":"3","author":"TF Outeiro","year":"2008","unstructured":"Outeiro TF et al (2008) Formation of Toxic Oligomeric \u03b1-Synuclein Species in Living Cells. PLoS ONE 3:e1867","journal-title":"PLoS ONE"},{"key":"1915_CR36","doi-asserted-by":"crossref","unstructured":"Jumper J et al (2021) Highly accurate protein structure prediction with AlphaFold. Nature 596","DOI":"10.1038\/s41586-021-03819-2"},{"key":"1915_CR37","doi-asserted-by":"publisher","first-page":"4545","DOI":"10.1093\/hmg\/ddt301","volume":"22","author":"YC Su","year":"2013","unstructured":"Su YC, Qi X (2013) Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet 22:4545\u20134561","journal-title":"Hum Mol Genet"},{"key":"1915_CR38","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.stem.2011.01.013","volume":"8","author":"HN Nguyen","year":"2011","unstructured":"Nguyen HN et al (2011) LRRK2 Mutant iPSC-Derived DA Neurons Demonstrate Increased Susceptibility to Oxidative Stress. Cell Stem Cell 8:267\u2013280","journal-title":"Cell Stem Cell"},{"key":"1915_CR39","doi-asserted-by":"publisher","first-page":"6216","DOI":"10.3390\/ijms23116216","volume":"23","author":"I Kawahata","year":"2022","unstructured":"Kawahata I, Finkelstein DI, Fukunaga K (2022) Pathogenic Impact of \u03b1-Synuclein Phosphorylation and Its Kinases in \u03b1-Synucleinopathies. Int J Mol Sci 23:6216","journal-title":"Int J Mol Sci"},{"key":"1915_CR40","doi-asserted-by":"publisher","first-page":"29739","DOI":"10.1074\/jbc.M600933200","volume":"281","author":"JP Anderson","year":"2006","unstructured":"Anderson JP et al (2006) Phosphorylation of Ser-129 Is the Dominant Pathological Modification of \u03b1-Synuclein in Familial and Sporadic Lewy Body Disease. J Biol Chem 281:29739\u201329752","journal-title":"J Biol Chem"},{"key":"1915_CR41","doi-asserted-by":"publisher","first-page":"16533","DOI":"10.1038\/s41598-017-15813-8","volume":"7","author":"M Karampetsou","year":"2017","unstructured":"Karampetsou M et al (2017) Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice. Sci Rep 7:16533","journal-title":"Sci Rep"},{"key":"1915_CR42","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1038\/s41467-018-03241-9","volume":"9","author":"T Ryan","year":"2018","unstructured":"Ryan T et al (2018) Cardiolipin exposure on the outer mitochondrial membrane modulates \u03b1-synuclein. Nat Commun 9:817","journal-title":"Nat Commun"},{"key":"1915_CR43","doi-asserted-by":"crossref","unstructured":"Lynch CJ, Adams SH (2014) Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol 10","DOI":"10.1038\/nrendo.2014.171"},{"key":"1915_CR44","doi-asserted-by":"crossref","unstructured":"Blackburn PR et al (2017) Maple syrup urine disease: Mechanisms and management. Appl Clin Genet 10","DOI":"10.2147\/TACG.S125962"},{"key":"1915_CR45","doi-asserted-by":"crossref","unstructured":"Strauss KA et al (2020) Branched-chain \u03b1-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Mol Genet Metab 129","DOI":"10.1016\/j.ymgme.2020.01.006"},{"key":"1915_CR46","doi-asserted-by":"crossref","unstructured":"Gao Q et al (2024) The association between branched-chain amino acid concentrations and the risk of autism spectrum disorder in preschool-aged children. Mol Neurobiol 61","DOI":"10.1007\/s12035-024-03965-4"},{"key":"1915_CR47","doi-asserted-by":"crossref","unstructured":"Li JL et al (2021) Mitochondrial Function and Parkinson\u2019s Disease: From the Perspective of the Electron Transport Chain. Front Mol Neurosci 14","DOI":"10.3389\/fnmol.2021.797833"},{"key":"1915_CR48","doi-asserted-by":"crossref","unstructured":"Read AD, Bentley RE, Archer SL, Dunham-Snary KJ (2021) Mitochondrial iron\u2013sulfur clusters: Structure, function, and an emerging role in vascular biology: Mitochondrial Fe-S Clusters \u2013 a review. Redox Biol 47","DOI":"10.1016\/j.redox.2021.102164"},{"key":"1915_CR49","doi-asserted-by":"crossref","unstructured":"Zhang Y et al (2022) Plasma branched-chain and aromatic amino acids correlate with the gut microbiota and severity of Parkinson\u2019s disease. Npj Park Dis 8","DOI":"10.1038\/s41531-022-00312-z"},{"key":"1915_CR50","doi-asserted-by":"crossref","unstructured":"Nguyen HN et al (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8","DOI":"10.1016\/j.stem.2011.01.013"},{"key":"1915_CR51","doi-asserted-by":"crossref","unstructured":"Wi\u015bniewski JR, Zougman A, Nagaraj N, Mann M (2009) Universal sample preparation method for proteome analysis. Nat Methods 6","DOI":"10.1038\/nmeth.1322"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-024-01915-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-024-01915-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-024-01915-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T03:04:49Z","timestamp":1734750289000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-024-01915-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,21]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["1915"],"URL":"https:\/\/doi.org\/10.1186\/s40478-024-01915-8","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,21]]},"assertion":[{"value":"3 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 December 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal experiments were conducted in accordance with protocols approved by Case Western Reserve University\u2019s Institutional Animal Care and Use Committee and were performed based on the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Sufficient procedures were employed to reduce the pain and discomfort of the mice during the experiments. Postmortem patient samples were obtained from the National Institutes of Health (NIH) NeuroBioBank under the approval of the Institutional Review Board (IRB) and Research Ethics Board. All brains were donated to the NBB by informed consent through the Brain and Tissue Repositories sites.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"198"}}