{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:54:12Z","timestamp":1780451652708,"version":"3.54.1"},"reference-count":76,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T00:00:00Z","timestamp":1708905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rossy Family Foundation","award":["40480"],"award-info":[{"award-number":["40480"]}]},{"name":"Edmond J. Safra Philanthropic Foundation","award":["40480"],"award-info":[{"award-number":["40480"]}]},{"name":"Canada Foundation for Innovation John Evans Leaders Fund program","award":["40480"],"award-info":[{"award-number":["40480"]}]},{"name":"Ontario Research Fund","award":["40480"],"award-info":[{"award-number":["40480"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lewy body diseases (LBDs) feature \u03b1-synuclein (\u03b1-syn)-containing Lewy bodies, with misfolded \u03b1-syn potentially propagating as seeds. Using a seeding amplification assay, we previously reported distinct \u03b1-syn seeding in LBD cases based on the area under seeding curves. This study revealed that LBD cases showing different \u03b1-syn seeding kinetics have distinct proteomics profiles, emphasizing disruptions in mitochondria and lipid metabolism in high-seeder cases. Though the mechanisms underlying LBD development are intricate, the factors influencing \u03b1-syn seeding activity remain elusive. To address this and complement our previous findings, we conducted targeted transcriptome analyses in the substantia nigra using the nanoString nCounter assay together with histopathological evaluations in high (n = 4) and low (n = 3) nigral \u03b1-syn seeders. Neuropathological findings (particularly the substantia nigra) were consistent between these groups and were characterized by neocortical LBD associated with Alzheimer\u2019s disease neuropathologic change. Among the 1811 genes assessed, we identified the top 20 upregulated and downregulated genes and pathways in \u03b1-syn high seeders compared with low seeders. Notably, alterations were observed in genes and pathways related to transmembrane transporters, lipid metabolism, and the ubiquitin\u2013proteasome system in the high \u03b1-syn seeders. In conclusion, our findings suggest that the molecular behavior of \u03b1-syn is the driving force in the neurodegenerative process affecting the substantia nigra through these identified pathways. These insights highlight their potential as therapeutic targets for attenuating LBD progression.<\/jats:p>","DOI":"10.3390\/ijms25052676","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T06:50:23Z","timestamp":1708930223000},"page":"2676","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Molecular Behavior of \u03b1-Synuclein Is Associated with Membrane Transport, Lipid Metabolism, and Ubiquitin\u2013Proteasome Pathways in Lewy Body Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Tomoya","family":"Kon","sequence":"first","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, 60 Leonard Ave., Toronto, ON M5T 0S8, Canada"},{"name":"Department of Neurology, Hirosaki University Graduate School of Medicine, 5 Zaifu, Hirosaki 036-8562, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seojin","family":"Lee","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, 60 Leonard Ave., Toronto, ON M5T 0S8, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, 200 Elizabeth St., Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6463-6321","authenticated-orcid":false,"given":"Ivan","family":"Martinez-Valbuena","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, 60 Leonard Ave., Toronto, ON M5T 0S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6780-1932","authenticated-orcid":false,"given":"Koji","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, 60 Leonard Ave., Toronto, ON M5T 0S8, Canada"},{"name":"Department of Legal Medicine, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Tanikawa","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, 60 Leonard Ave., Toronto, ON M5T 0S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony E.","family":"Lang","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, 60 Leonard Ave., Toronto, ON M5T 0S8, Canada"},{"name":"Edmond J Safra Program in Parkinson\u2019s Disease and Rossy Progressive Supranuclear Palsy Centre, Toronto Western Hospital, 399 Bathurst St., Toronto, ON M5T 2S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3841-5511","authenticated-orcid":false,"given":"Gabor G.","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, 60 Leonard Ave., Toronto, ON M5T 0S8, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, 200 Elizabeth St., Toronto, ON M5G 2C4, Canada"},{"name":"Edmond J Safra Program in Parkinson\u2019s Disease and Rossy Progressive Supranuclear Palsy Centre, Toronto Western Hospital, 399 Bathurst St., Toronto, ON M5T 2S8, Canada"},{"name":"Laboratory Medicine Program, University Health Network, 200 Elizabeth St., Toronto, ON M5G 2C4, Canada"},{"name":"Krembil Brain Institute, University of Toronto, 60 Leonard Ave., Toronto, ON M5T 0S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/neup.12597","article-title":"Neuropathology of Lewy body disease: Clinicopathological crosstalk between typical and atypical cases","volume":"40","author":"Kon","year":"2020","journal-title":"Neuropathology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nrneurol.2012.242","article-title":"100 years of Lewy pathology","volume":"9","author":"Goedert","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1111\/j.1440-1789.2007.00803.x","article-title":"The Lewy body in Parkinson\u2019s disease: Molecules implicated in the formation and degradation of alpha-synuclein aggregates","volume":"27","author":"Wakabayashi","year":"2007","journal-title":"Neuropathology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s00401-022-02403-w","article-title":"Consequences of variability in alpha-synuclein fibril structure on strain biology","volume":"143","author":"Holec","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1007\/s00401-020-02157-3","article-title":"The structural differences between patient-derived alpha-synuclein strains dictate characteristics of Parkinson\u2019s disease, multiple system atrophy and dementia with Lewy bodies","volume":"139","author":"Gelders","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1126\/science.1227157","article-title":"Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice","volume":"338","author":"Luk","year":"2012","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41582-020-0333-7","article-title":"Protein transmission in neurodegenerative disease","volume":"16","author":"Peng","year":"2020","journal-title":"Nat. Rev. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00401-022-02453-0","article-title":"alpha-Synuclein molecular behavior and nigral proteomic profiling distinguish subtypes of Lewy body disorders","volume":"144","author":"Swinkin","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40035-022-00283-4","article-title":"Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy","volume":"11","author":"Visanji","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/ejn.13760","article-title":"A review of genome-wide transcriptomics studies in Parkinson\u2019s disease","volume":"47","author":"Borrageiro","year":"2018","journal-title":"Eur. J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.nbd.2017.04.004","article-title":"Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson\u2019s disease","volume":"109","author":"Rocha","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1017\/neu.2020.13","article-title":"Systematic review of gene expression studies in people with Lewy body dementia","volume":"32","author":"Chowdhury","year":"2020","journal-title":"Acta Neuropsychiatr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1007\/s00702-004-0212-1","article-title":"Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion\/cellular matrix and vesicle trafficking genes","volume":"111","author":"Grunblatt","year":"2004","journal-title":"J. Neural. Transm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1002\/mds.22184","article-title":"Neuronal gene expression correlates of Parkinson\u2019s disease with dementia","volume":"23","author":"Stamper","year":"2008","journal-title":"Mov. Disord."},{"key":"ref_15","first-page":"89","article-title":"Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms","volume":"8","author":"Konetti","year":"2017","journal-title":"Front. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1111\/bpa.12511","article-title":"Transcriptional network analysis in frontal cortex in Lewy body diseases with focus on dementia with Lewy bodies","volume":"28","author":"Santpere","year":"2018","journal-title":"Brain Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jagp.2019.06.007","article-title":"Postmortem Cortical Transcriptomics of Lewy Body Dementia Reveal Mitochondrial Dysfunction and Lack of Neuroinflammation","volume":"28","author":"Rajkumar","year":"2020","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00401-020-02181-3","article-title":"Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease","volume":"140","author":"Kim","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2148820","DOI":"10.1155\/2021\/2148820","article-title":"Complementary Transcriptomic and Proteomic Analysis in the Substantia Nigra of Parkinson\u2019s Disease","volume":"2021","author":"Dong","year":"2021","journal-title":"Dis. Markers"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e10668","DOI":"10.7717\/peerj.10668","article-title":"An integrated analysis of lncRNA and mRNA expression profiles in the kidneys of mice with lupus nephritis","volume":"9","author":"Wang","year":"2021","journal-title":"PeerJ"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s40291-023-00653-2","article-title":"Nucleic Acid Quality Assessment is Critical to the Success of the Oncomine Dx Target Test for Lung Cancer","volume":"27","author":"Nagakubo","year":"2023","journal-title":"Mol. Diagn. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nbt1385","article-title":"Direct multiplexed measurement of gene expression with color-coded probe pairs","volume":"26","author":"Geiss","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1471-4159.2006.03731.x","article-title":"Amino acid sequence motifs and mechanistic features of the membrane translocation of alpha-synuclein","volume":"97","author":"Ahn","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4595","DOI":"10.1021\/bi0121353","article-title":"Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson\u2019s disease-linked mutations and occurs by a pore-like mechanism","volume":"41","author":"Volles","year":"2002","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.15252\/embj.201593411","article-title":"Tunneling nanotubes spread fibrillar alpha-synuclein by intercellular trafficking of lysosomes","volume":"35","author":"Abounit","year":"2016","journal-title":"EMBO J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1111\/tra.12859","article-title":"alpha-Synuclein fibrils explore actin-mediated macropinocytosis for cellular entry into model neuroblastoma neurons","volume":"23","author":"Hivare","year":"2022","journal-title":"Traffic"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Stillwell, W. (2016). An Introduction to Biological Membranes: Composition, Structure and Function, Elsevier. [2nd ed.].","DOI":"10.1016\/B978-0-444-63772-7.00001-4"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1093\/hmg\/ddu099","article-title":"Parkinson\u2019s disease-linked human PARK9\/ATP13A2 maintains zinc homeostasis and promotes alpha-Synuclein externalization via exosomes","volume":"23","author":"Kong","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Si, J., Van den Haute, C., Lobbestael, E., Martin, S., van Veen, S., Vangheluwe, P., and Baekelandt, V. (2021). ATP13A2 Regulates Cellular alpha-Synuclein Multimerization, Membrane Association, and Externalization. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052689"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1620\/tjem.242.63","article-title":"Membrane Trafficking Illuminates a Path to Parkinson\u2019s Disease","volume":"242","author":"Hasegawa","year":"2017","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/0896-6273(95)90302-X","article-title":"The precursor protein of non-A beta component of Alzheimer\u2019s disease amyloid is a presynaptic protein of the central nervous system","volume":"14","author":"Iwai","year":"1995","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nature10324","article-title":"alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation","volume":"477","author":"Bartels","year":"2011","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6365","DOI":"10.1523\/JNEUROSCI.20-17-06365.2000","article-title":"Subcellular localization of wild-type and Parkinson\u2019s disease-associated mutant alpha -synuclein in human and transgenic mouse brain","volume":"20","author":"Kahle","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1126\/science.aan6160","article-title":"Structural basis of membrane disruption and cellular toxicity by alpha-synuclein oligomers","volume":"358","author":"Fusco","year":"2017","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19366","DOI":"10.1021\/ja2029848","article-title":"Mechanism of membrane interaction and disruption by alpha-synuclein","volume":"133","author":"Reynolds","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.neuron.2013.09.004","article-title":"The function of alpha-synuclein","volume":"79","author":"Bendor","year":"2013","journal-title":"Neuron"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1016\/j.jmb.2006.12.044","article-title":"Relationships between the sequence of alpha-synuclein and its membrane affinity, fibrillization propensity, and yeast toxicity","volume":"366","author":"Volles","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5512","DOI":"10.1038\/s41467-022-33252-6","article-title":"Small soluble alpha-synuclein aggregates are the toxic species in Parkinson\u2019s disease","volume":"13","author":"Emin","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4845","DOI":"10.1529\/biophysj.108.130997","article-title":"Soluble amyloid beta-oligomers affect dielectric membrane properties by bilayer insertion and domain formation: Implications for cell toxicity","volume":"95","author":"Valincius","year":"2008","journal-title":"Biophys. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/pmic.201300342","article-title":"Proteomic analysis of human substantia nigra identifies novel candidates involved in Parkinson\u2019s disease pathogenesis","volume":"14","author":"Licker","year":"2014","journal-title":"Proteomics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17625","DOI":"10.1038\/srep17625","article-title":"Synchrotron FTIR micro-spectroscopy for structural analysis of Lewy bodies in the brain of Parkinson\u2019s disease patients","volume":"5","author":"Araki","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/s41593-019-0423-2","article-title":"Lewy pathology in Parkinson\u2019s disease consists of crowded organelles and lipid membranes","volume":"22","author":"Shahmoradian","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1042\/EBC20200067","article-title":"Mammalian lipids: Structure, synthesis and function","volume":"65","author":"Cockcroft","year":"2021","journal-title":"Essays Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41531-019-0095-3","article-title":"Endogenous alpha-synuclein monomers, oligomers and resulting pathology: Let\u2019s talk about the lipids in the room","volume":"5","author":"Killinger","year":"2019","journal-title":"NPJ Parkinsons Dis."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Musteikyte, G., Jayaram, A.K., Xu, C.K., Vendruscolo, M., Krainer, G., and Knowles, T.P.J. (2021). Interactions of alpha-synuclein oligomers with lipid membranes. Biochim. Biophys. Acta Biomembr., 1863.","DOI":"10.1016\/j.bbamem.2020.183536"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/nchembio.1750","article-title":"Lipid vesicles trigger alpha-synuclein aggregation by stimulating primary nucleation","volume":"11","author":"Galvagnion","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5379","DOI":"10.1007\/s12035-022-02897-1","article-title":"Role of Ubiquitin-Proteasome and Autophagy-Lysosome Pathways in alpha-Synuclein Aggregate Clearance","volume":"59","author":"Sahoo","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1093\/brain\/awm318","article-title":"The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson\u2019s disease","volume":"131","author":"Pan","year":"2008","journal-title":"Brain"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1083\/jcb.201003122","article-title":"alpha-Synuclein impairs macroautophagy: Implications for Parkinson\u2019s disease","volume":"190","author":"Winslow","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4257","DOI":"10.1007\/s12035-022-02851-1","article-title":"Exploring the Role of Ubiquitin-Proteasome System in Parkinson\u2019s Disease","volume":"59","author":"Behl","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1093\/jnen\/62.12.1241","article-title":"Morphogenesis of Lewy bodies: Dissimilar incorporation of alpha-synuclein, ubiquitin, and p62","volume":"62","author":"Kuusisto","year":"2003","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/BF00334457","article-title":"An early cytoplasmic change before Lewy body maturation: An ultrastructural study of the substantia nigra from an autopsy case of juvenile parkinsonism","volume":"85","author":"Hayashida","year":"1993","journal-title":"Acta Neuropathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e2312306120","DOI":"10.1073\/pnas.2312306120","article-title":"Lysophagy protects against propagation of alpha-synuclein aggregation through ruptured lysosomal vesicles","volume":"121","author":"Kakuda","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1186\/s40478-023-01687-7","article-title":"Neuronal SNCA transcription during Lewy body formation","volume":"11","author":"Kon","year":"2023","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/s41576-020-0258-4","article-title":"mRNAs, proteins and the emerging principles of gene expression control","volume":"21","author":"Buccitelli","year":"2020","journal-title":"Nat. Rev. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/ana.10846","article-title":"Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications","volume":"55","author":"Farrer","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4094","DOI":"10.1093\/hmg\/dds238","article-title":"MAPT expression and splicing is differentially regulated by brain region: Relation to genotype and implication for tauopathies","volume":"21","author":"Trabzuni","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1007\/s00702-019-02025-9","article-title":"alpha-Synuclein in Parkinson\u2019s disease: Causal or bystander?","volume":"126","author":"Riederer","year":"2019","journal-title":"J. Neural. Transm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1212\/01.WNL.0000127517.33208.F4","article-title":"Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication","volume":"62","author":"Miller","year":"2004","journal-title":"Neurology"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Gry, M., Rimini, R., Stromberg, S., Asplund, A., Ponten, F., Uhlen, M., and Nilsson, P. (2009). Correlations between RNA and protein expression profiles in 23 human cell lines. BMC Genom., 10.","DOI":"10.1186\/1471-2164-10-365"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Edfors, F., Danielsson, F., Hallstrom, B.M., Kall, L., Lundberg, E., Ponten, F., Forsstrom, B., and Uhlen, M. (2016). Gene-specific correlation of RNA and protein levels in human cells and tissues. Mol. Syst. Biol., 12.","DOI":"10.15252\/msb.20167144"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1097\/NEN.0000000000000190","article-title":"Effects of postmortem interval on biomolecule integrity in the brain","volume":"74","author":"Nagy","year":"2015","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","article-title":"Staging of brain pathology related to sporadic Parkinson\u2019s disease","volume":"24","author":"Braak","year":"2003","journal-title":"Neurobiol. Aging"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00401-020-02255-2","article-title":"Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: A multi-centre study","volume":"141","author":"Attems","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-011-0910-3","article-title":"National Institute on Aging-Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease: A practical approach","volume":"123","author":"Montine","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","article-title":"Phases of A beta-deposition in the human brain and its relevance for the development of AD","volume":"58","author":"Thal","year":"2002","journal-title":"Neurology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1212\/01.wnl.0000187889.17253.b1","article-title":"Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium","volume":"65","author":"McKeith","year":"2005","journal-title":"Neurology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"595","DOI":"10.3233\/JAD-215675","article-title":"Patterns of Mixed Pathologies in Down Syndrome","volume":"87","author":"Ichimata","year":"2022","journal-title":"J. Alzheimers Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1093\/jnen\/nlac117","article-title":"Significant contralaterality of temporal-predominant neuroastroglial tauopathy and FTLD-TDP type C presenting with the right temporal variant FTD","volume":"82","author":"Tanaka","year":"2023","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/ana.26540","article-title":"Cell-Specific Dysregulation of Iron and Oxygen Homeostasis as a Novel Pathophysiology in PSP","volume":"93","author":"Lee","year":"2023","journal-title":"Ann. Neurol."},{"key":"ref_72","unstructured":"(2023, December 07). Available online: https:\/\/www.rstudio.com\/about\/rstudio-open-source-packages\/."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_75","unstructured":"Korotkevich, D., Sukhov, V., Budin, N., Shpak, B., Artyomov, M.N., and Sergushichev, A. (2021). Fast gene set enrichment analysis. bioRxiv, 1\u201329."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2016). ggplot2: Elegant Graphics for Data Analysis, Springer. [2nd ed.].","DOI":"10.1007\/978-3-319-24277-4"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/2676\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:04:49Z","timestamp":1760105089000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/2676"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,26]]},"references-count":76,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ijms25052676"],"URL":"https:\/\/doi.org\/10.3390\/ijms25052676","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,26]]}}}