{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T21:07:31Z","timestamp":1793912851465,"version":"4.8.0"},"reference-count":91,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T00:00:00Z","timestamp":1714348800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T00:00:00Z","timestamp":1714348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100006475","name":"Bergens Forskningsstiftelse","doi-asserted-by":"publisher","award":["BFS2017REK05"],"award-info":[{"award-number":["BFS2017REK05"]}],"id":[{"id":"10.13039\/501100006475","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Idiopathic Parkinson\u2019s disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.<\/jats:p>","DOI":"10.1038\/s41467-024-47867-4","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T12:02:40Z","timestamp":1714392160000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Mitochondrial complex I deficiency stratifies idiopathic Parkinson\u2019s disease"],"prefix":"10.1038","volume":"15","author":[{"given":"Irene H.","family":"Fl\u00f8nes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6514-561X","authenticated-orcid":false,"given":"Lilah","family":"Toker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagny Ann","family":"Sandnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Castelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sepideh","family":"Mostafavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nj\u00e5l","family":"Lura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omnia","family":"Shadad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2469-142X","authenticated-orcid":false,"given":"Erika","family":"Fernandez-Vizarra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e8lia","family":"Painous","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"P\u00e9rez-Soriano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaroslau","family":"Compta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4068-8578","authenticated-orcid":false,"given":"Laura","family":"Molina-Porcel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0630-2870","authenticated-orcid":false,"given":"Guido","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7230-6426","authenticated-orcid":false,"given":"Ole-Bj\u00f8rn","family":"Tysnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2427-8130","authenticated-orcid":false,"given":"Christian","family":"D\u00f6lle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1766-4108","authenticated-orcid":false,"given":"Gonzalo S.","family":"Nido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0341-5191","authenticated-orcid":false,"given":"Charalampos","family":"Tzoulis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,29]]},"reference":[{"key":"47867_CR1","doi-asserted-by":"publisher","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","volume":"397","author":"BR Bloem","year":"2021","unstructured":"Bloem, B. R., Okun, M. S. & Klein, C. Parkinson\u2019s disease. Lancet 397, 2284\u20132303 (2021).","journal-title":"Lancet"},{"key":"47867_CR2","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","volume":"386","author":"LV Kalia","year":"2015","unstructured":"Kalia, L. V. & Lang, A. E. Parkinson\u2019s disease. Lancet 386, 896\u2013912 (2015).","journal-title":"Lancet"},{"key":"47867_CR3","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/nrneurol.2014.226","volume":"11","author":"D Athauda","year":"2015","unstructured":"Athauda, D. & Foltynie, T. The ongoing pursuit of neuroprotective therapies in Parkinson disease. Nat. Rev. Neurol. 11, 25\u201340 (2015).","journal-title":"Nat. Rev. Neurol."},{"key":"47867_CR4","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1002\/mds.26913","volume":"32","author":"AJ Espay","year":"2017","unstructured":"Espay, A. J. et al. Biomarker-driven phenotyping in Parkinson disease: a translational missing link in disease-modifying clinical trials. Mov. Disord. J. Mov. Disord. Soc. 32, 319\u2013324 (2017).","journal-title":"Mov. Disord. J. Mov. Disord. Soc."},{"key":"47867_CR5","doi-asserted-by":"publisher","first-page":"a009258","DOI":"10.1101\/cshperspect.a009258","volume":"2","author":"DW Dickson","year":"2012","unstructured":"Dickson, D. W. Parkinson\u2019s Disease and Parkinsonism: Neuropathology. Cold Spring Harb. Perspect. Med. 2, a009258\u2013a009258 (2012).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"47867_CR6","doi-asserted-by":"publisher","first-page":"eaam6003","DOI":"10.1126\/scitranslmed.aam6003","volume":"10","author":"AS Chen-Plotkin","year":"2018","unstructured":"Chen-Plotkin, A. S. et al. Finding Useful Biomarkers for Parkinson\u2019s Disease. Sci. Transl. Med. 10, eaam6003 (2018).","journal-title":"Sci. Transl. Med."},{"key":"47867_CR7","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1111\/ejn.14094","volume":"49","author":"JC Greenland","year":"2019","unstructured":"Greenland, J. C., Williams-Gray, C. H. & Barker, R. A. The clinical heterogeneity of Parkinson\u2019s disease and its therapeutic implications. Eur. J. Neurosci. 49, 328\u2013338 (2019).","journal-title":"Eur. J. Neurosci."},{"key":"47867_CR8","doi-asserted-by":"publisher","first-page":"2314","DOI":"10.1002\/mds.21844","volume":"22","author":"B Dubois","year":"2007","unstructured":"Dubois, B. et al. Diagnostic procedures for Parkinson\u2019s disease dementia: Recommendations from the movement disorder society task force. Mov. Disord. 22, 2314\u20132324 (2007).","journal-title":"Mov. Disord."},{"key":"47867_CR9","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/S1353-8020(99)00051-6","volume":"6","author":"MC Schiess","year":"2000","unstructured":"Schiess, M. C. et al. Parkinson\u2019s disease subtypes: clinical classification and ventricular cerebrospinal fluid analysis. Parkinsonism Relat. Disord. 6, 69\u201376 (2000).","journal-title":"Parkinsonism Relat. Disord."},{"key":"47867_CR10","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.1212\/WNL.40.10.1529","volume":"40","author":"J Jankovic","year":"1990","unstructured":"Jankovic, J. et al. Variable expression of Parkinson\u2019s disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology 40, 1529\u20131534 (1990).","journal-title":"Neurology"},{"key":"47867_CR11","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.pneurobio.2018.09.003","volume":"177","author":"A Gr\u00fcnewald","year":"2019","unstructured":"Gr\u00fcnewald, A., Kumar, K. R. & Sue, C. M. New insights into the complex role of mitochondria in Parkinson\u2019s disease. Prog. Neurobiol. 177, 73\u201393 (2019).","journal-title":"Prog. Neurobiol."},{"key":"47867_CR12","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1016\/S0140-6736(89)92366-0","volume":"1","author":"AH Schapira","year":"1989","unstructured":"Schapira, A. H. et al. Mitochondrial complex I deficiency in Parkinson\u2019s disease. Lancet 1, 1269 (1989).","journal-title":"Lancet"},{"key":"47867_CR13","doi-asserted-by":"publisher","first-page":"147434","DOI":"10.1016\/j.brainres.2021.147434","volume":"1767","author":"N Subrahmanian","year":"2021","unstructured":"Subrahmanian, N. & LaVoie, M. J. Is there a special relationship between complex I activity and nigral neuronal loss in Parkinson\u2019s disease? A critical reappraisal. Brain Res. 1767, 147434 (2021).","journal-title":"Brain Res."},{"key":"47867_CR14","doi-asserted-by":"publisher","first-page":"874596","DOI":"10.3389\/fcell.2022.874596","volume":"10","author":"IH Fl\u00f8nes","year":"2022","unstructured":"Fl\u00f8nes, I. H. & Tzoulis, C. Mitochondrial Respiratory Chain Dysfunction\u2014A Hallmark Pathology of Idiopathic Parkinson\u2019s Disease? Front. Cell Dev. Biol. 10, 874596 (2022).","journal-title":"Front. Cell Dev. Biol."},{"key":"47867_CR15","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/S0006-291X(86)80483-1","volume":"134","author":"RR Ramsay","year":"1986","unstructured":"Ramsay, R. R., Salach, J. I. & Singer, T. P. Uptake of the neurotoxin 1-methyl-4-phenylpyridine (MPP+) by mitochondria and its relation to the inhibition of the mitochondrial oxidation of NAD+-linked substrates by MPP+. Biochem. Biophys. Res. Commun. 134, 743\u2013748 (1986).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"47867_CR16","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1126\/science.6823561","volume":"219","author":"JW Langston","year":"1983","unstructured":"Langston, J. W., Ballard, P., Tetrud, J. W. & Irwin, I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979\u2013980 (1983).","journal-title":"Science"},{"key":"47867_CR17","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1038\/81834","volume":"3","author":"R Betarbet","year":"2000","unstructured":"Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson\u2019s disease. Nat. Neurosci. 3, 1301\u20131306 (2000).","journal-title":"Nat. Neurosci."},{"key":"47867_CR18","doi-asserted-by":"publisher","first-page":"e13187","DOI":"10.15252\/emmm.202013187","volume":"12","author":"K Reinson","year":"2020","unstructured":"Reinson, K. & \u00d5unap, K. Complex I deficiency and Leigh syndrome through the eyes of a clinician. EMBO Mol. Med. 12, e13187 (2020).","journal-title":"EMBO Mol. Med."},{"key":"47867_CR19","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1136\/jnnp.59.2.160","volume":"59","author":"EK Nikoskelainen","year":"1995","unstructured":"Nikoskelainen, E. K. et al. Leber\u2019s \u201cplus\u201d: neurological abnormalities in patients with Leber\u2019s hereditary optic neuropathy. J. Neurol. Neurosurg. Psychiatry 59, 160\u2013164 (1995).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"47867_CR20","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.mito.2012.08.004","volume":"12","author":"N Balafkan","year":"2012","unstructured":"Balafkan, N. et al. Number of CAG repeats in POLG1 and its association with Parkinson disease in the Norwegian population. Mitochondrion 12, 640\u2013643 (2012).","journal-title":"Mitochondrion"},{"key":"47867_CR21","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.neulet.2009.11.037","volume":"469","author":"K Gaweda-Walerych","year":"2010","unstructured":"Gaweda-Walerych, K. et al. Mitochondrial transcription factor A variants and the risk of Parkinson\u2019s disease. Neurosci. Lett. 469, 24\u201329 (2010).","journal-title":"Neurosci. Lett."},{"key":"47867_CR22","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1093\/brain\/116.6.1451","volume":"116","author":"R Benecke","year":"1993","unstructured":"Benecke, R., Str\u00fcmper, P. & Weiss, H. Electron transfer complexes I and IV of platelets are abnormal in Parkinson\u2019s disease but normal in Parkinson-plus syndromes. Brain 116, 1451\u20131463 (1993).","journal-title":"Brain"},{"key":"47867_CR23","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/BF02257619","volume":"4","author":"H Yoshino","year":"1992","unstructured":"Yoshino, H., Nakagawa-Hattori, Y., Kondo, T. & Mizuno, Y. Mitochondrial complex I and II activities of lymphocytes and platelets in Parkinson\u2019s disease. J. Neural Transm. Park. Dis. Dement. Sect. 4, 27\u201334 (1992).","journal-title":"J. Neural Transm. Park. Dis. Dement. Sect."},{"key":"47867_CR24","doi-asserted-by":"publisher","first-page":"101772","DOI":"10.1016\/j.pneurobio.2020.101772","volume":"187","author":"PJ Carling","year":"2020","unstructured":"Carling, P. J. et al. Deep phenotyping of peripheral tissue facilitates mechanistic disease stratification in sporadic Parkinson\u2019s disease. Prog. Neurobiol. 187, 101772 (2020).","journal-title":"Prog. Neurobiol."},{"key":"47867_CR25","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.jns.2004.02.003","volume":"220","author":"K Winkler-Stuck","year":"2004","unstructured":"Winkler-Stuck, K., Wiedemann, F. R., Wallesch, C.-W. & Kunz, W. S. Effect of coenzyme Q10 on the mitochondrial function of skin fibroblasts from Parkinson patients. J. Neurol. Sci. 220, 41\u201348 (2004).","journal-title":"J. Neurol. Sci."},{"key":"47867_CR26","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/nature19754","volume":"538","author":"DA Stroud","year":"2016","unstructured":"Stroud, D. A. et al. Accessory subunits are integral for assembly and function of human mitochondrial complex I. Nature 538, 123\u2013126 (2016).","journal-title":"Nature"},{"key":"47867_CR27","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1007\/s00401-017-1794-7","volume":"135","author":"IH Fl\u00f8nes","year":"2018","unstructured":"Fl\u00f8nes, I. H. et al. Neuronal complex I deficiency occurs throughout the Parkinson\u2019s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage. Acta Neuropathol. 135, 409\u2013425 (2018).","journal-title":"Acta Neuropathol."},{"key":"47867_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13548","volume":"7","author":"C D\u00f6lle","year":"2016","unstructured":"D\u00f6lle, C. et al. Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease. Nat. Commun. 7, 13548 (2016).","journal-title":"Nat. Commun."},{"key":"47867_CR29","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1038\/ng1769","volume":"38","author":"A Bender","year":"2006","unstructured":"Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet 38, 515\u2013517 (2006).","journal-title":"Nat. Genet"},{"key":"47867_CR30","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1001\/archneur.60.3.337","volume":"60","author":"C Zarow","year":"2003","unstructured":"Zarow, C., Lyness, S. A., Mortimer, J. A. & Chui, H. C. Neuronal Loss Is Greater in the Locus Coeruleus Than Nucleus Basalis and Substantia Nigra in Alzheimer and Parkinson Diseases. Arch. Neurol. 60, 337\u2013341 (2003).","journal-title":"Arch. Neurol."},{"key":"47867_CR31","doi-asserted-by":"publisher","first-page":"721","DOI":"10.3945\/ajcn.115.113548","volume":"102","author":"DL Streiner","year":"2015","unstructured":"Streiner, D. L. Best (but oft-forgotten) practices: the multiple problems of multiplicity-whether and how to correct for many statistical tests. Am. J. Clin. Nutr. 102, 721\u2013728 (2015).","journal-title":"Am. J. Clin. Nutr."},{"key":"47867_CR32","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/j.biopsych.2018.07.010","volume":"84","author":"L Toker","year":"2018","unstructured":"Toker, L., Mancarci, B. O., Tripathy, S. & Pavlidis, P. Transcriptomic Evidence for Alterations in Astrocytes and Parvalbumin Interneurons in Subjects With Bipolar Disorder and Schizophrenia. Biol. Psychiatry 84, 787\u2013796 (2018).","journal-title":"Biol. Psychiatry"},{"key":"47867_CR33","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/s40478-020-00932-7","volume":"8","author":"GS Nido","year":"2020","unstructured":"Nido, G. S. et al. Common gene expression signatures in Parkinson\u2019s disease are driven by changes in cell composition. Acta Neuropathol. Commun. 8, 55 (2020).","journal-title":"Acta Neuropathol. Commun."},{"key":"47867_CR34","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13024-021-00450-7","volume":"16","author":"L Toker","year":"2021","unstructured":"Toker, L. et al. Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson\u2019s disease brain. Mol. Neurodegener. 16, 31 (2021).","journal-title":"Mol. Neurodegener."},{"key":"47867_CR35","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1038\/33416","volume":"392","author":"T Kitada","year":"1998","unstructured":"Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605\u2013608 (1998).","journal-title":"Nature"},{"key":"47867_CR36","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1126\/science.aaf1204","volume":"352","author":"BB Lake","year":"2016","unstructured":"Lake, B. B. et al. Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain. Science 352, 1586\u20131590 (2016).","journal-title":"Science"},{"key":"47867_CR37","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.tins.2004.06.005","volume":"27","author":"RG Shulman","year":"2004","unstructured":"Shulman, R. G., Rothman, D. L., Behar, K. L. & Hyder, F. Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci. 27, 489\u2013495 (2004).","journal-title":"Trends Neurosci."},{"key":"47867_CR38","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/j.bbabio.2008.05.443","volume":"1777","author":"RU Pathak","year":"2008","unstructured":"Pathak, R. U. & Davey, G. P. Complex I and energy thresholds in the brain. Biochim. Biophys. Acta 1777, 777\u2013782 (2008).","journal-title":"Biochim. Biophys. Acta"},{"key":"47867_CR39","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1038\/s41586-021-04059-0","volume":"599","author":"P Gonz\u00e1lez-Rodr\u00edguez","year":"2021","unstructured":"Gonz\u00e1lez-Rodr\u00edguez, P. et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 599, 650\u2013656 (2021).","journal-title":"Nature"},{"key":"47867_CR40","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1007\/s00429-022-02531-9","volume":"227","author":"JT Boonstra","year":"2022","unstructured":"Boonstra, J. T., McGurran, H., Temel, Y. & Jahanshahi, A. Nigral neuropathology of Parkinson\u2019s motor subtypes coincide with circuitopathies: a scoping review. Brain Struct. Funct. 227, 2231\u20132242 (2022).","journal-title":"Brain Struct. Funct."},{"key":"47867_CR41","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.cmet.2022.02.001","volume":"34","author":"B Brakedal","year":"2022","unstructured":"Brakedal, B. et al. The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson\u2019s disease. Cell Metab. 34, 396\u2013407.e6 (2022).","journal-title":"Cell Metab."},{"key":"47867_CR42","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1042\/bj20021594","volume":"370","author":"R Rossignol","year":"2003","unstructured":"Rossignol, R. et al. Mitochondrial threshold effects. Biochem J. 370, 751\u2013762 (2003).","journal-title":"Biochem J."},{"key":"47867_CR43","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1038\/ng1778","volume":"38","author":"Y Kraytsberg","year":"2006","unstructured":"Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet 38, 518\u2013520 (2006).","journal-title":"Nat. Genet"},{"key":"47867_CR44","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1002\/ana.25127","volume":"83","author":"MC Rocha","year":"2018","unstructured":"Rocha, M. C. et al. Pathological mechanisms underlying single large-scale mitochondrial DNA deletions. Ann. Neurol. 83, 115\u2013130 (2018).","journal-title":"Ann. Neurol."},{"key":"47867_CR45","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.bbadis.2006.12.009","volume":"1772","author":"S Verkaart","year":"2007","unstructured":"Verkaart, S. & Koopman, W. J. H. van Emst-de Vries SE, et al. Superoxide production is inversely related to complex I activity in inherited complex I deficiency. Biochim. Biophys. Acta BBA Mol. Basis Dis. 1772, 373\u2013381 (2007).","journal-title":"Biochim. Biophys. Acta BBA Mol. Basis Dis."},{"key":"47867_CR46","doi-asserted-by":"publisher","first-page":"175","DOI":"10.3390\/genes9040175","volume":"9","author":"G Zsurka","year":"2018","unstructured":"Zsurka, G., Peeva, V., Kotlyar, A. & Kunz, W. S. Is There Still Any Role for Oxidative Stress in Mitochondrial DNA-Dependent Aging? Genes 9, 175 (2018).","journal-title":"Genes"},{"key":"47867_CR47","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1111\/nan.12238","volume":"42","author":"NZ Lax","year":"2016","unstructured":"Lax, N. Z. et al. Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease. Neuropathol. Appl. Neurobiol. 42, 180\u2013193 (2016).","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"47867_CR48","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-023-01195-2","volume":"15","author":"L Toker","year":"2023","unstructured":"Toker, L., Nido, G. S. & Tzoulis, C. Not every estimate counts \u2013 evaluation of cell composition estimation approaches in brain bulk tissue data. Genome Med. 15, 41 (2023).","journal-title":"Genome Med."},{"key":"47867_CR49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/ejn.13760","volume":"47","author":"G Borrageiro","year":"2018","unstructured":"Borrageiro, G. et al. A review of genome-wide transcriptomics studies in Parkinson\u2019s disease. Eur. J. Neurosci. 47, 1\u201316 (2018).","journal-title":"Eur. J. Neurosci."},{"key":"47867_CR50","doi-asserted-by":"publisher","first-page":"328","DOI":"10.3389\/fnins.2019.00328","volume":"13","author":"I Alecu","year":"2019","unstructured":"Alecu, I. & Bennett, S. A. L. Dysregulated Lipid Metabolism and Its Role in \u03b1-Synucleinopathy in Parkinson\u2019s Disease. Front. Neurosci. 13, 328 (2019).","journal-title":"Front. Neurosci."},{"key":"47867_CR51","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s13024-021-00425-8","volume":"16","author":"Y Shao","year":"2021","unstructured":"Shao, Y. et al. Comprehensive metabolic profiling of Parkinson\u2019s disease by liquid chromatography-mass spectrometry. Mol. Neurodegener. 16, 4 (2021).","journal-title":"Mol. Neurodegener."},{"key":"47867_CR52","doi-asserted-by":"publisher","first-page":"2047","DOI":"10.1038\/s42255-023-00930-8","volume":"5","author":"A Picca","year":"2023","unstructured":"Picca, A. et al. Mitophagy in human health, ageing and disease. Nat. Metab. 5, 2047\u20132061 (2023).","journal-title":"Nat. Metab."},{"key":"47867_CR53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17876-0","volume":"11","author":"D Agarwal","year":"2020","unstructured":"Agarwal, D. et al. A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders. Nat. Commun. 11, 4183 (2020).","journal-title":"Nat. Commun."},{"key":"47867_CR54","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1136\/jnnp.2008.168211","volume":"80","author":"G Alves","year":"2009","unstructured":"Alves, G. et al. Incidence of Parkinson\u2019s disease in Norway: the Norwegian ParkWest. Study J. Neurol. Neurosurg. Psychiatry 80, 851\u2013857 (2009).","journal-title":"Study J. Neurol. Neurosurg. Psychiatry"},{"key":"47867_CR55","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1002\/mds.64","volume":"33","author":"JJ Gaare","year":"2018","unstructured":"Gaare, J. J. et al. Rare genetic variation in mitochondrial pathways influences the risk for Parkinson\u2019s disease: Mitochondrial Pathways In PD. Mov. Disord. 33, 1591\u20131600 (2018).","journal-title":"Mov. Disord."},{"key":"47867_CR56","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1002\/mds.22340","volume":"23","author":"CG Goetz","year":"2008","unstructured":"Goetz, C. G. et al. Movement Disorder Society-sponsored revision of the Unified Parkinson\u2019s Disease Rating Scale (MDS-UPDRS): Scale presentation and clinimetric testing results: MDS-UPDRS: Clinimetric Assessment. Mov. Disord. 23, 2129\u20132170 (2008).","journal-title":"Mov. Disord."},{"key":"47867_CR57","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","volume":"12","author":"MF Folstein","year":"1975","unstructured":"Folstein, M. F., Folstein, S. E. & McHugh, P. R. \u201cMini-mental state\u201d. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189\u2013198 (1975).","journal-title":"J. Psychiatr. Res."},{"key":"47867_CR58","doi-asserted-by":"publisher","first-page":"e12942","DOI":"10.1111\/bpa.12942","volume":"31","author":"S Borrego-\u00c9cija","year":"2021","unstructured":"Borrego-\u00c9cija, S. et al. Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants. Brain Pathol. Zur. Switz. 31, e12942 (2021).","journal-title":"Brain Pathol. Zur. Switz."},{"key":"47867_CR59","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","volume":"24","author":"H Braak","year":"2003","unstructured":"Braak, H. et al. Staging of brain pathology related to sporadic Parkinson\u2019s disease. Neurobiol. Aging 24, 197\u2013211 (2003).","journal-title":"Neurobiol. Aging"},{"key":"47867_CR60","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1007\/s00401-006-0127-z","volume":"112","author":"H Braak","year":"2006","unstructured":"Braak, H. et al. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 112, 389\u2013404 (2006).","journal-title":"Acta Neuropathol."},{"key":"47867_CR61","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s00401-020-02255-2","volume":"141","author":"J Attems","year":"2021","unstructured":"Attems, J. et al. Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study. Acta Neuropathol. 141, 159\u2013172 (2021).","journal-title":"Acta Neuropathol."},{"key":"47867_CR62","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1111\/j.1750-3639.2008.00147.x","volume":"18","author":"I Alafuzoff","year":"2008","unstructured":"Alafuzoff, I. et al. Staging of Neurofibrillary Pathology in Alzheimer\u2019s Disease: A Study of the BrainNet Europe Consortium. Brain Pathol. 18, 484\u2013496 (2008).","journal-title":"Brain Pathol."},{"key":"47867_CR63","doi-asserted-by":"publisher","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","volume":"58","author":"DR Thal","year":"2002","unstructured":"Thal, D. R., R\u00fcb, U., Orantes, M. & Braak, H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791\u20131800 (2002).","journal-title":"Neurology"},{"key":"47867_CR64","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1016\/S1474-4422(09)70238-8","volume":"8","author":"DW Dickson","year":"2009","unstructured":"Dickson, D. W. et al. Neuropathological assessment of Parkinson\u2019s disease: refining the diagnostic criteria. Lancet Neurol. 8, 1150\u20131157 (2009).","journal-title":"Lancet Neurol."},{"key":"47867_CR65","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.12688\/f1000research.7563.2","volume":"4","author":"C Soneson","year":"2016","unstructured":"Soneson, C., Love, M. I. & Robinson, M. D. Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Research 4, 1521 (2016).","journal-title":"F1000Research"},{"key":"47867_CR66","doi-asserted-by":"crossref","unstructured":"Mancarci B. O., et al. Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data. eNeuro 4, ENEURO.0212-0217.2017 (2017).","DOI":"10.1523\/ENEURO.0212-17.2017"},{"key":"47867_CR67","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1038\/nprot.2010.78","volume":"5","author":"J Gillis","year":"2010","unstructured":"Gillis, J., Mistry, M. & Pavlidis, P. Gene function analysis in complex data sets using ErmineJ. Nat. Protoc. 5, 1148\u20131159 (2010).","journal-title":"Nat. Protoc."},{"key":"47867_CR68","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/75556","volume":"25","author":"M Ashburner","year":"2000","unstructured":"Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25\u201329 (2000).","journal-title":"Nat. Genet."},{"key":"47867_CR69","doi-asserted-by":"publisher","first-page":"277D","DOI":"10.1093\/nar\/gkh063","volume":"32","author":"M Kanehisa","year":"2004","unstructured":"Kanehisa, M. The KEGG resource for deciphering the genome. Nucleic Acids Res. 32, 277D\u2013280D (2004).","journal-title":"Nucleic Acids Res."},{"key":"47867_CR70","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","volume":"27","author":"A Liberzon","year":"2011","unstructured":"Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739\u20131740 (2011).","journal-title":"Bioinformatics"},{"key":"47867_CR71","doi-asserted-by":"publisher","first-page":"D1541","DOI":"10.1093\/nar\/gkaa1011","volume":"49","author":"S Rath","year":"2021","unstructured":"Rath, S. et al. MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations. Nucleic Acids Res. 49, D1541\u2013D1547 (2021).","journal-title":"Nucleic Acids Res."},{"key":"47867_CR72","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.3317","volume":"12","author":"D Kim","year":"2015","unstructured":"Kim, D., Langmead, B. & Salzberg, S. L. HISAT: a fast spliced aligner with low memory requirements. Nat. Methods 12, 357\u2013360 (2015).","journal-title":"Nat. Methods"},{"key":"47867_CR73","doi-asserted-by":"crossref","first-page":"11 10 1","DOI":"10.1002\/0471250953.bi1110s43","volume":"43","author":"GA Van der Auwera","year":"2013","unstructured":"Van der Auwera, G. A. et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinforma. 43, 11 10 1\u201333 (2013).","journal-title":"Curr. Protoc. Bioinforma."},{"key":"47867_CR74","doi-asserted-by":"publisher","first-page":"W58","DOI":"10.1093\/nar\/gkw233","volume":"44","author":"H Weissensteiner","year":"2016","unstructured":"Weissensteiner, H. et al. HaploGrep 2: mitochondrial haplogroup classification in the era of high-throughput sequencing. Nucleic Acids Res. 44, W58\u2013W63 (2016).","journal-title":"Nucleic Acids Res."},{"key":"47867_CR75","doi-asserted-by":"publisher","first-page":"5747","DOI":"10.3390\/ijms22115747","volume":"22","author":"A D\u00fcr","year":"2021","unstructured":"D\u00fcr, A., Huber, N. & Parson, W. Fine-Tuning Phylogenetic Alignment and Haplogrouping of mtDNA Sequences. Int. J. Mol. Sci. 22, 5747 (2021).","journal-title":"Int. J. Mol. Sci."},{"key":"47867_CR76","doi-asserted-by":"publisher","first-page":"2156","DOI":"10.1093\/bioinformatics\/btr330","volume":"27","author":"P Danecek","year":"2011","unstructured":"Danecek, P. et al. The variant call format and VCFtools. Bioinformatics 27, 2156\u20132158 (2011).","journal-title":"Bioinformatics"},{"key":"47867_CR77","doi-asserted-by":"publisher","DOI":"10.1186\/s13742-015-0047-8","volume":"4","author":"CC Chang","year":"2015","unstructured":"Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015).","journal-title":"Gigascience"},{"key":"47867_CR78","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/nature02168","volume":"426","author":"RA Gibbs","year":"2003","unstructured":"Gibbs, R. A. et al. The International HapMap Project. Nature 426, 789\u2013796 (2003).","journal-title":"Nature"},{"key":"47867_CR79","doi-asserted-by":"publisher","first-page":"e190","DOI":"10.1371\/journal.pgen.0020190","volume":"2","author":"N Patterson","year":"2006","unstructured":"Patterson, N., Price, A. L. & Reich, D. Population Structure and Eigenanalysis. PLOS Genet 2, e190 (2006).","journal-title":"PLOS Genet"},{"key":"47867_CR80","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/ng1847","volume":"38","author":"AL Price","year":"2006","unstructured":"Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet 38, 904\u2013909 (2006).","journal-title":"Nat. Genet"},{"key":"47867_CR81","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1016\/j.neuron.2020.06.021","volume":"107","author":"H Lee","year":"2020","unstructured":"Lee, H. et al. Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation. Neuron 107, 891\u2013908.e8 (2020).","journal-title":"Neuron"},{"key":"47867_CR82","unstructured":"Fleming, S. J., et al. Unsupervised removal of systematic background noise from droplet-based single-cell experiments using CellBender. Nat Methods 791699, https:\/\/www.biorxiv.org\/content\/10.1101\/791699v2 (2022)."},{"key":"47867_CR83","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","volume":"184","author":"Y Hao","year":"2021","unstructured":"Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573\u20133587.e29 (2021).","journal-title":"Cell"},{"key":"47867_CR84","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05083-x","volume":"9","author":"JA Griffiths","year":"2018","unstructured":"Griffiths, J. A. et al. Detection and removal of barcode swapping in single-cell RNA-seq data. Nat. Commun. 9, 2667 (2018).","journal-title":"Nat. Commun."},{"key":"47867_CR85","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.cels.2019.03.003","volume":"8","author":"CS McGinnis","year":"2019","unstructured":"McGinnis, C. S., Murrow, L. M. & Gartner, Z. J. DoubletFinder: Doublet Detection in Single-Cell RNA Sequencing Data Using Artificial Nearest Neighbors. Cell Syst. 8, 329\u2013337.e4 (2019).","journal-title":"Cell Syst."},{"key":"47867_CR86","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0844-5","volume":"16","author":"G Finak","year":"2015","unstructured":"Finak, G. et al. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol. 16, 278 (2015).","journal-title":"Genome Biol."},{"key":"47867_CR87","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21038-1","volume":"12","author":"KD Zimmerman","year":"2021","unstructured":"Zimmerman, K. D., Espeland, M. A. & Langefeld, C. D. A practical solution to pseudoreplication bias in single-cell studies. Nat. Commun. 12, 738 (2021).","journal-title":"Nat. Commun."},{"key":"47867_CR88","unstructured":"Korotkevich, G., et al. Fast gene set enrichment analysis. Biorxiv https:\/\/www.biorxiv.org\/content\/10.1101\/060012v3 (2021)."},{"key":"47867_CR89","unstructured":"Nido, G. CI deficiency PD stratification; Available from: https:\/\/repo-prod.prod.sagebase.org\/repo\/v1\/doi\/locate?id=syn53502566&type=ENTITY&version=1 (2024)."},{"key":"47867_CR90","unstructured":"gsnido. gsnido\/pd_complex-i_stratification: Code release for publication. Available from: https:\/\/zenodo.org\/records\/10715023 (2024)."},{"key":"47867_CR91","doi-asserted-by":"publisher","DOI":"10.1038\/s41597-019-0254-8","volume":"6","author":"BL Edlow","year":"2019","unstructured":"Edlow, B. L. et al. 7 Tesla MRI of the ex vivo human brain at 100 micron resolution. Sci. Data 6, 244 (2019).","journal-title":"Sci. Data"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47867-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47867-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47867-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T13:05:39Z","timestamp":1714395939000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47867-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,29]]},"references-count":91,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["47867"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-47867-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.09.22.558615","asserted-by":"object"}]},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,29]]},"assertion":[{"value":"2 August 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3631"}}