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Clinical presentations of MSA overlap with other parkinsonian disorders, such as Parkinson\u2019s disease (PD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP), posing challenges in early diagnosis. Numerous studies have reported alterations in DNA methylation in neurodegenerative diseases, with candidate loci being identified in various parkinsonian disorders including MSA, PD, and PSP. Although MSA and PSP present with substantial white matter pathology, alterations in white matter have also been reported in PD. However, studies comparing the DNA methylation architectures of white matter in these diseases are lacking. We therefore aimed to investigate genome-wide DNA methylation patterns in the frontal lobe white matter of individuals with MSA (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200917), PD (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200917), and PSP (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200916) along with controls (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200915) using the Illumina EPIC array, to identify shared and disease-specific DNA methylation alterations. Genome-wide DNA methylation profiling of frontal lobe white matter in the three parkinsonian disorders revealed substantial commonalities in DNA methylation alterations in MSA, PD, and PSP. We further used weighted gene correlation network analysis to identify disease-associated co-methylation signatures and identified dysregulation in processes relating to Wnt signaling, signal transduction, endoplasmic reticulum stress, mitochondrial processes, RNA interference, and endosomal transport to be shared between these parkinsonian disorders. Our overall analysis points toward more similarities in DNA methylation patterns between MSA and PD, both synucleinopathies, compared to that between MSA and PD with PSP, which is a tauopathy. Our results also highlight several shared DNA methylation changes and pathways indicative of converging molecular mechanisms in the white matter contributing toward neurodegeneration in all three parkinsonian disorders.\n                  <\/jats:p>","DOI":"10.1007\/s00401-024-02764-4","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T06:02:23Z","timestamp":1720764143000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["DNA methylation patterns in the frontal lobe white matter of multiple system atrophy, Parkinson\u2019s disease, and progressive supranuclear palsy: a cross-comparative investigation"],"prefix":"10.1007","volume":"148","author":[{"given":"Megha","family":"Murthy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Fodder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Miki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naiomi","family":"Rambarack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"De Pablo Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lasse","family":"Pihlstr\u00f8m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Mill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas T.","family":"Warner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammaryn","family":"Lashley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9090-7690","authenticated-orcid":false,"given":"Concei\u00e7\u00e3o","family":"Bettencourt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,12]]},"reference":[{"key":"2764_CR1","doi-asserted-by":"publisher","first-page":"1921","DOI":"10.1002\/hbm.22302","volume":"35","author":"F Agosta","year":"2014","unstructured":"Agosta F, Canu E, Stefanova E, Sarro L, Tomic A, Spica V et al (2014) Mild cognitive impairment in Parkinson\u2019s disease is associated with a distributed pattern of brain white matter damage. 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