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We evaluated mitochondrial DNA copy number from human brain-derived WGS data using the fastMitoCalc tool. 341 Parkinson\u2019s Disease cerebellum samples were compared with 74 age-matched controls from the North American Brain Expression Consortium. Parkinson\u2019s Disease cerebellum had significantly higher mitochondrial DNA copy number compared with controls (P = 4.15e\u20137), and this effect was reproducible in four of five brain banks when analysis was restricted to each resource that contributed Parkinson\u2019s Disease samples to this genetic dataset. Follow-on analyses of 128 Parkinson\u2019s Disease cerebellum samples and 33 controls that had paired neuropathology data and clinical scores demonstrated a significant increase in mitochondrial DNA copy number with Unified Staging System for Lewy Body disorders stages and Unified Parkinson\u2019s Disease Rating Scale (off meds) motor scores. Analysis of Lewy Body scores from ten brain regions showed cerebellum mitochondrial DNA copy number increased upon pathological infestation of \u03b1-synuclein aggregates in the brainstem and limbic system but did not increase after late-stage neocortical involvement. This genetics dataset supports previous observations of cerebellum activation in Parkinson\u2019s Disease and suggests mitochondrial DNA copy number may increase to support this regional activation as a compensatory mechanism to pathology or motor symptoms.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf296","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:02:28Z","timestamp":1755648148000},"source":"Crossref","is-referenced-by-count":3,"title":["Cerebellum mitochondrial DNA copy number is increased in Parkinson\u2019s disease"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2307-3365","authenticated-orcid":false,"given":"Talia","family":"Beglarian","sequence":"first","affiliation":[{"name":"Department of Translational Genomics, Keck School of Medicine, University of Southern California , 1450 Biggy St. NRT 2502, Los Angeles, CA 90033 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R","family":"Tyrpak","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Keck School of Medicine, University of Southern California , 1450 Biggy St. NRT 2502, Los Angeles, CA 90033 ,","place":["USA"]},{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California , Los Angeles, CA 90089 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Raphael","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3626-1654","authenticated-orcid":false,"given":"John Andrew","family":"MacKay","sequence":"additional","affiliation":[{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California , Los Angeles, CA 90089 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6623-0429","authenticated-orcid":false,"given":"Sonja W","family":"Scholz","sequence":"additional","affiliation":[{"name":"Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke , Bethesda, MD 20892 ,","place":["USA"]},{"name":"Department of Neurology, Johns Hopkins University Medical Center , Baltimore, MD 21287 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan J","family":"Traynor","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Research Section, National Institute on Aging , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn S","family":"Albert","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University Medical Center , Baltimore, MD 21287 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana S","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University Medical Center , Baltimore, MD 21287 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6459-0893","authenticated-orcid":false,"given":"Ted M","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University Medical Center , Baltimore, MD 21287 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C","family":"Troncoso","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University Medical Center , Baltimore, MD 21287 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