{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T09:02:21Z","timestamp":1780045341705,"version":"3.53.1"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":22,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Fond d\u2019enseignement et de recherche du cercle du congr\u00e8s de la Facult\u00e9 de pharmacie\u2013Universit\u00e9 Laval, Canada"},{"DOI":"10.13039\/501100009307","name":"Parkinson Canada","doi-asserted-by":"publisher","award":["2017-1110"],"award-info":[{"award-number":["2017-1110"]}],"id":[{"id":"10.13039\/501100009307","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009307","name":"Parkinson Canada","doi-asserted-by":"publisher","award":["2017-1110"],"award-info":[{"award-number":["2017-1110"]}],"id":[{"id":"10.13039\/501100009307","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT 168927"],"award-info":[{"award-number":["PJT 168927"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","award":["#34480"],"award-info":[{"award-number":["#34480"]}],"id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Parkinsons Dis."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Parkinson\u2019s disease (PD) is characterized by a loss of dopaminergic neurons and accumulation of \u03b1-synuclein (\u03b1-syn)-containing Lewy bodies in the substantia nigra (SN) pars compacta. Mutations in the gene coding for the protein parkin cause a form of autosomal recessive juvenile parkinsonism, but its role in idiopathic PD is poorly understood. Here, to investigate parkin changes in the SN in PD, we established a clinicopathology research platform comparing PD patients (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200924) with Controls (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200921). We first confirmed the massive loss of dopamine (DA) levels (\u221296%) in the putamen of PD patients, using HPLC\/electrochemistry. Higher levels of phosphorylated \u03b1-syn (\u03b1synP129) (23-fold) were observed in the SN of PD patients by Western immunoblotting. In formic acid extracts, an increase in the insoluble oligomeric form of parkin migrating at 260\u2009kDa was observed (+\u200949%) in the SN of PD patients, along with lower levels of the 55\u2009kDa monomeric form (\u221247%). These changes in parkin were specific for the SN, and not observed in the putamen, parietal cortex and cerebellum. High molecular weight parkin correlated with \u03b1synP129 levels and dopamine loss and was more prominently found in PD patients with levodopa-induced dyskinesias. Additional studies in animal models suggest that the aggregation of parkin is not a direct consequence of dopaminergic depletion or \u03b1syn overproduction, but a component of PD cellular pathophysiology. Taken together, the results reported herein show that, beside dopamine loss and increased \u03b1synP129, neurodegeneration in idiopathic PD is associated with a conversion of parkin into an insoluble high molecular weight form in the SN.\n                  <\/jats:p>","DOI":"10.1038\/s41531-026-01371-2","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:17:26Z","timestamp":1778127446000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High molecular weight insoluble parkin in the substantia nigra of patients with idiopathic Parkinson\u2019s disease"],"prefix":"10.1038","volume":"12","author":[{"given":"Cyntia","family":"Tremblay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Pshevorskiy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalie J.","family":"Cottez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8na L.","family":"Denis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Emond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Morissette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali H.","family":"Rajput","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Th\u00e9r\u00e8se","family":"Di Paolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Rajput","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Calon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"1371_CR1","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1002\/mds.10343","volume":"18","author":"F Calon","year":"2003","unstructured":"Calon, F. et al. Changes of GABA receptors and dopamine turnover in the postmortem brains of Parkinsonians with levodopa-induced motor complications. Mov. Disord. 18, 241\u2013253 (2003).","journal-title":"Mov. Disord."},{"key":"1371_CR2","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1212\/WNL.47.3.718","volume":"47","author":"JM Wilson","year":"1996","unstructured":"Wilson, J. M. et al. Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson\u2019s disease. Neurology 47, 718\u2013726 (1996).","journal-title":"Neurology"},{"key":"1371_CR3","unstructured":"Hornykiewicz, O. & Kish, S. J. Biochemical pathophysiology of Parkinson\u2019s disease. Adv. Neurol. 45, 19\u201334 (1987)."},{"key":"1371_CR4","doi-asserted-by":"crossref","unstructured":"Ehringer, H. & Hornykiewicz, O. Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Parkinsonism Relat. Disord. 4, 53\u201357 (1998).","DOI":"10.1016\/S1353-8020(98)00012-1"},{"key":"1371_CR5","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1002\/mds.27360","volume":"33","author":"AE Lang","year":"2018","unstructured":"Lang, A. E. & Espay, A. J. Disease Modification in Parkinson\u2019s Disease: Current Approaches, Challenges, and Future Considerations. Mov. Disord. 33, 660\u2013677 (2018).","journal-title":"Mov. Disord."},{"key":"1371_CR6","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":"1371_CR7","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1001\/jama.2019.22360","volume":"323","author":"MJ Armstrong","year":"2020","unstructured":"Armstrong, M. J. & Okun, M. S. Diagnosis and treatment of Parkinson disease: a review. JAMA 323, 548\u2013560 (2020).","journal-title":"JAMA"},{"key":"1371_CR8","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1212\/WNL.0000000000009107","volume":"94","author":"AJ Espay","year":"2020","unstructured":"Espay, A. J. et al. Disease modification and biomarker development in Parkinson disease: Revision or reconstruction. Neurology 94, 481\u2013494 (2020).","journal-title":"Neurology"},{"key":"1371_CR9","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1016\/S1474-4422(15)00006-X","volume":"14","author":"B Dehay","year":"2015","unstructured":"Dehay, B. et al. Targeting \u03b1-synuclein for treatment of Parkinson\u2019s disease: mechanistic and therapeutic considerations. Lancet Neurol. 14, 855\u2013866 (2015).","journal-title":"Lancet Neurol."},{"key":"1371_CR10","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1111\/jnc.14810","volume":"150","author":"D Sulzer","year":"2019","unstructured":"Sulzer, D. & Edwards, R. H. The physiological role of \u03b1-synuclein and its relationship to Parkinson\u2019s Disease. J. Neurochem 150, 475\u2013486 (2019).","journal-title":"J. Neurochem"},{"key":"1371_CR11","doi-asserted-by":"publisher","first-page":"4374","DOI":"10.1074\/jbc.M115.705095","volume":"291","author":"F Samuel","year":"2016","unstructured":"Samuel, F. et al. Effects of Serine 129 Phosphorylation on \u03b1-Synuclein Aggregation, Membrane Association, and Internalization. J. Biol. Chem. 291, 4374\u20134385 (2016).","journal-title":"J. Biol. Chem."},{"key":"1371_CR12","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/ncb748","volume":"4","author":"H Fujiwara","year":"2002","unstructured":"Fujiwara, H. et al. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160\u2013164 (2002).","journal-title":"Nat. Cell Biol."},{"key":"1371_CR13","doi-asserted-by":"publisher","first-page":"39","DOI":"10.3233\/JPD-160779","volume":"6","author":"A Oueslati","year":"2016","unstructured":"Oueslati, A. Implication of Alpha-Synuclein Phosphorylation at S129 in Synucleinopathies: What Have We Learned in the Last Decade? J. Parkinsons Dis. 6, 39\u201351 (2016).","journal-title":"J. Parkinsons Dis."},{"key":"1371_CR14","doi-asserted-by":"crossref","unstructured":"Estaun-Panzano, J., Arotcarena, M.-L. & Bezard, E. Monitoring \u03b1-synuclein aggregation. Neurobiol. Dis. 176, 105966 (2023).","DOI":"10.1016\/j.nbd.2022.105966"},{"key":"1371_CR15","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1126\/science.1090278","volume":"302","author":"AB Singleton","year":"2003","unstructured":"Singleton, A. B. et al. alpha-Synuclein locus triplication causes Parkinson\u2019s disease. Science 302, 841 (2003).","journal-title":"Science"},{"key":"1371_CR16","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/s41531-021-00203-9","volume":"7","author":"LMA Oliveira","year":"2021","unstructured":"Oliveira, L. M. A. et al. Alpha-synuclein research: defining strategic moves in the battle against Parkinson\u2019s disease. NPJ Parkinsons Dis. 7, 65 (2021).","journal-title":"NPJ Parkinsons Dis."},{"key":"1371_CR17","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1001\/jamaneurol.2022.4193","volume":"80","author":"AJ Espay","year":"2023","unstructured":"Espay, A. J. & Okun, M. S. Abandoning the Proteinopathy Paradigm in Parkinson Disease. JAMA Neurol. 80, 123\u2013124 (2023).","journal-title":"JAMA Neurol."},{"key":"1371_CR18","doi-asserted-by":"crossref","unstructured":"Espay, A. J. & Lees, A. J. Loss of monomeric alpha-synuclein (synucleinopenia) and the origin of Parkinson\u2019s disease. Parkinsonism Relat. Disord. 122, 106077 (2024).","DOI":"10.1016\/j.parkreldis.2024.106077"},{"key":"1371_CR19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2109617119","volume":"119","author":"SS Ghanem","year":"2022","unstructured":"Ghanem, S. S. et al. \u03b1-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity. Proc. Natl. Acad. Sci. USA 119, e2109617119 (2022).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"1371_CR20","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1016\/j.tins.2024.05.005","volume":"47","author":"N Ramalingam","year":"2024","unstructured":"Ramalingam, N., Haass, C. & Dettmer, U. Physiological roles of \u03b1-synuclein serine-129 phosphorylation - not an oxymoron. Trends Neurosci. 47, 480\u2013490 (2024).","journal-title":"Trends Neurosci."},{"key":"1371_CR21","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/nrneurol.2013.132","volume":"9","author":"J Trinh","year":"2013","unstructured":"Trinh, J. & Farrer, M. Advances in the genetics of Parkinson disease. Nat. Rev. Neurol. 9, 445\u2013454 (2013).","journal-title":"Nat. Rev. Neurol."},{"key":"1371_CR22","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1002\/ana.24335","volume":"77","author":"V Escott-Price","year":"2015","unstructured":"Escott-Price, V. et al. Polygenic risk of Parkinson disease is correlated with disease age at onset. Ann. Neurol. 77, 582\u2013591 (2015).","journal-title":"Ann. Neurol."},{"key":"1371_CR23","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1002\/mds.27802","volume":"34","author":"S Heinzel","year":"2019","unstructured":"Heinzel, S. et al. MDS TFOTDOPD. Update of the MDS research criteria for prodromal Parkinson\u2019s disease. Mov. Disord. 34, 1464\u20131470 (2019).","journal-title":"Mov. Disord."},{"key":"1371_CR24","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/s00018-024-05262-8","volume":"81","author":"L Clausen","year":"2024","unstructured":"Clausen, L. et al. PRKN-linked familial Parkinson\u2019s disease: cellular and molecular mechanisms of disease-linked variants. Cell Mol. Life Sci. 81, 223 (2024).","journal-title":"Cell Mol. Life Sci."},{"key":"1371_CR25","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":"1371_CR26","doi-asserted-by":"publisher","first-page":"2811","DOI":"10.1093\/hmg\/ddz080","volume":"28","author":"W Yi","year":"2019","unstructured":"Yi, W. et al. The landscape of Parkin variants reveals pathogenic mechanisms and therapeutic targets in Parkinson\u2019s disease. Hum. Mol. Genet 28, 2811\u20132825 (2019).","journal-title":"Hum. Mol. Genet"},{"key":"1371_CR27","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1002\/ana.25787","volume":"88","author":"S Lesage","year":"2020","unstructured":"Lesage, S. et al. Characterization of Recessive Parkinson Disease in a Large Multicenter Study. Ann. Neurol. 88, 843\u2013850 (2020).","journal-title":"Ann. Neurol."},{"key":"1371_CR28","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/s41531-024-00677-3","volume":"10","author":"PJ Menon","year":"2024","unstructured":"Menon, P. J. et al. Genotype-phenotype correlation in PRKN-associated Parkinson\u2019s disease. NPJ Parkinsons Dis. 10, 72 (2024).","journal-title":"NPJ Parkinsons Dis."},{"key":"1371_CR29","doi-asserted-by":"crossref","unstructured":"Connelly, E. M., Frankel, K. S. & Shaw, G. S. Parkin and mitochondrial signalling. Cell Signal 106, 110631 (2023).","DOI":"10.1016\/j.cellsig.2023.110631"},{"key":"1371_CR30","doi-asserted-by":"publisher","first-page":"4589","DOI":"10.1007\/s00018-019-03203-4","volume":"76","author":"AN Bayne","year":"2019","unstructured":"Bayne, A. N. & Trempe, J. F. Mechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond. Cell Mol. Life Sci. 76, 4589\u20134611 (2019).","journal-title":"Cell Mol. Life Sci."},{"key":"1371_CR31","doi-asserted-by":"publisher","DOI":"10.1186\/s13062-017-0176-3","volume":"12","author":"J Chakraborty","year":"2017","unstructured":"Chakraborty, J., Basso, V. & Ziviani, E. Post translational modification of Parkin. Biol. Direct 12, 6 (2017).","journal-title":"Biol. Direct"},{"key":"1371_CR32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI179633","volume":"134","author":"R Han","year":"2024","unstructured":"Han, R. et al. Deficiency of parkin causes neurodegeneration and accumulation of pathological \u03b1-synuclein in monkey models. J. Clin. Invest 134, e179633 (2024).","journal-title":"J. Clin. Invest"},{"key":"1371_CR33","doi-asserted-by":"publisher","first-page":"13771","DOI":"10.1074\/jbc.M707494200","volume":"283","author":"JS Schlehe","year":"2008","unstructured":"Schlehe, J. S. et al. Aberrant folding of pathogenic Parkin mutants: aggregation versus degradation. J. Biol. Chem. 283, 13771\u201313779 (2008).","journal-title":"J. Biol. Chem."},{"key":"1371_CR34","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.nbd.2003.08.011","volume":"14","author":"W-J Gu","year":"2003","unstructured":"Gu, W.-J. et al. The C289G and C418R missense mutations cause rapid sequestration of human Parkin into insoluble aggregates. Neurobiol. Dis. 14, 357\u2013364 (2003).","journal-title":"Neurobiol. Dis."},{"key":"1371_CR35","doi-asserted-by":"crossref","unstructured":"LaVoie, M. J., Ostaszewski, B. L., Weihofen, A., Schlossmacher, M. G. & Selkoe, D. J. Dopamine covalently modifies and functionally inactivates parkin. Nat. Med. 11, 1214\u20131221 (2005).","DOI":"10.1038\/nm1314"},{"key":"1371_CR36","doi-asserted-by":"publisher","first-page":"3885","DOI":"10.1093\/hmg\/ddi413","volume":"14","author":"C Wang","year":"2005","unstructured":"Wang, C. et al. Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin\u2019s protective function. Hum. Mol. Genet 14, 3885\u20133897 (2005).","journal-title":"Hum. Mol. Genet"},{"key":"1371_CR37","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1007\/s00401-021-02285-4","volume":"141","author":"JM Tokarew","year":"2021","unstructured":"Tokarew, J. M. et al. Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites. Acta Neuropathol. 141, 725\u2013754 (2021).","journal-title":"Acta Neuropathol."},{"key":"1371_CR38","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202012095","volume":"220","author":"N Panicker","year":"2021","unstructured":"Panicker, N., Ge, P., Dawson, V. L. & Dawson, T. M. The cell biology of Parkinson\u2019s disease. J. Cell Biol. 220, e202012095 (2021).","journal-title":"J. Cell Biol."},{"key":"1371_CR39","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1007\/s00702-017-1742-7","volume":"124","author":"N Hattori","year":"2017","unstructured":"Hattori, N. & Mizuno, Y. Twenty years since the discovery of the parkin gene. J. Neural Transm. (Vienna) 124, 1037\u20131054 (2017).","journal-title":"J. Neural Transm. (Vienna)"},{"key":"1371_CR40","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1007\/s40263-022-00973-7","volume":"36","author":"J Patel","year":"2022","unstructured":"Patel, J., Panicker, N., Dawson, V. L. & Dawson, T. M. Cell Biology of Parkin: Clues to the Development of New Therapeutics for Parkinson\u2019s Disease. CNS Drugs 36, 1249\u20131267 (2022).","journal-title":"CNS Drugs"},{"key":"1371_CR41","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/s41583-024-00812-2","volume":"25","author":"R Coukos","year":"2024","unstructured":"Coukos, R. & Krainc, D. Key genes and convergent pathogenic mechanisms in Parkinson disease. Nat. Rev. Neurosci. 25, 393\u2013413 (2024).","journal-title":"Nat. Rev. Neurosci."},{"key":"1371_CR42","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1111\/jnc.13696","volume":"139","author":"D Toulorge","year":"2016","unstructured":"Toulorge, D., Schapira, A. H. & Hajj, R. Molecular changes in the postmortem parkinsonian brain. J. Neurochem 139, 127\u201358 (2016).","journal-title":"J. Neurochem"},{"key":"1371_CR43","doi-asserted-by":"crossref","unstructured":"Lonskaya, I., Hebron, M. L., Algarzae, N. K., Desforges, N. & Moussa, C. E.-H. Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson\u2019s disease. Neuroscience 232, 90\u2013105 (2013).","DOI":"10.1016\/j.neuroscience.2012.12.018"},{"key":"1371_CR44","doi-asserted-by":"crossref","unstructured":"Muntan\u00e9, G., Ferrer, I. & Martinez-Vicente, M. \u03b1-synuclein phosphorylation and truncation are normal events in the adult human brain. Neuroscience 200, 106\u2013119 (2012).","DOI":"10.1016\/j.neuroscience.2011.10.042"},{"key":"1371_CR45","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.nbd.2006.08.021","volume":"25","author":"Y Chu","year":"2007","unstructured":"Chu, Y. & Kordower, J. H. Age-associated increases of alpha-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: Is this the target for Parkinson\u2019s disease? Neurobiol. Dis. 25, 134\u2013149 (2007).","journal-title":"Neurobiol. Dis."},{"key":"1371_CR46","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1002\/1531-8257(199905)14:3<417::AID-MDS1005>3.0.CO;2-X","volume":"14","author":"M Neystat","year":"1999","unstructured":"Neystat, M. et al. Alpha-synuclein expression in substantia nigra and cortex in Parkinson\u2019s disease. Mov. Disord. 14, 417\u2013422 (1999).","journal-title":"Mov. Disord."},{"key":"1371_CR47","doi-asserted-by":"crossref","unstructured":"Gigu\u00e8re, N., Burke Nanni, S. & Trudeau, L.-E. On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson\u2019s Disease. Front. Neurol. 9, 455 (2018).","DOI":"10.3389\/fneur.2018.00455"},{"key":"1371_CR48","doi-asserted-by":"crossref","unstructured":"Gonzalez-Rodriguez, P., Zampese, E. & Surmeier, D. J. Selective neuronal vulnerability in Parkinson\u2019s disease. Prog. Brain Res. 252, 61\u201389 (2020).","DOI":"10.1016\/bs.pbr.2020.02.005"},{"key":"1371_CR49","doi-asserted-by":"publisher","first-page":"18676","DOI":"10.1073\/pnas.0508052102","volume":"102","author":"WW Smith","year":"2005","unstructured":"Smith, W. W. et al. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl. Acad. Sci. USA 102, 18676\u201318681 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"1371_CR50","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/s41531-023-00544-7","volume":"9","author":"J-M Taymans","year":"2023","unstructured":"Taymans, J.-M. et al. Perspective on the current state of the LRRK2 field. NPJ Parkinsons Dis. 9, 104 (2023).","journal-title":"NPJ Parkinsons Dis."},{"key":"1371_CR51","doi-asserted-by":"crossref","unstructured":"Nguyen, A. P. T., Nguyen, L. T. N., Stokke, B. A. & Quinn, C. C. Roles of LRRK2 and its orthologs in protecting against neurodegeneration and neurodevelopmental defects. Front. Cell Dev. Biol. 13, (2025).","DOI":"10.3389\/fcell.2025.1569733"},{"key":"1371_CR52","doi-asserted-by":"publisher","first-page":"691","DOI":"10.3390\/cells11040691","volume":"11","author":"M Morissette","year":"2022","unstructured":"Morissette, M., Bourque, M., Tremblay, M. -\u00c8 & Di Paolo, T. Prevention of L-Dopa-Induced Dyskinesias by MPEP Blockade of Metabotropic Glutamate Receptor 5 Is Associated with Reduced Inflammation in the Brain of Parkinsonian Monkeys. Cells 11, 691 (2022).","journal-title":"Cells"},{"key":"1371_CR53","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.nbd.2011.09.009","volume":"45","author":"M Bousquet","year":"2012","unstructured":"Bousquet, M. et al. High-fat diet exacerbates MPTP-induced dopaminergic degeneration in mice. Neurobiol. Dis. 45, 529\u2013538 (2012).","journal-title":"Neurobiol. Dis."},{"key":"1371_CR54","doi-asserted-by":"crossref","unstructured":"Morin, N. et al. MPEP, an mGlu5 receptor antagonist, reduces the development of L-DOPA-induced motor complications in de novo parkinsonian monkeys: biochemical correlates. Neuropharmacology 66, 355\u2013364 (2013).","DOI":"10.1016\/j.neuropharm.2012.07.036"},{"key":"1371_CR55","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.expneurol.2017.12.002","volume":"301","author":"K Coulombe","year":"2018","unstructured":"Coulombe, K. et al. Impact of DHA intake in a mouse model of synucleinopathy. Exp. Neurol. 301, 39\u201349 (2018).","journal-title":"Exp. Neurol."},{"key":"1371_CR56","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1212\/WNL.0b013e3181ae7af1","volume":"73","author":"AH Rajput","year":"2009","unstructured":"Rajput, A. H., Voll, A., Rajput, M. L., Robinson, C. A. & Rajput, A. Course in Parkinson disease subtypes: A 39-year clinicopathologic study. Neurology 73, 206\u2013212 (2009).","journal-title":"Neurology"},{"key":"1371_CR57","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/s41582-021-00486-9","volume":"17","author":"D Berg","year":"2021","unstructured":"Berg, D. et al. Prodromal Parkinson disease subtypes - key to understanding heterogeneity. Nat. Rev. Neurol. 17, 349\u2013361 (2021).","journal-title":"Nat. Rev. Neurol."},{"key":"1371_CR58","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1111\/j.1471-4159.2005.03023.x","volume":"93","author":"C Wang","year":"2005","unstructured":"Wang, C. et al. Alterations in the solubility and intracellular localization of parkin by several familial Parkinson\u2019s disease-linked point mutations. J. Neurochem 93, 422\u2013431 (2005).","journal-title":"J. Neurochem"},{"key":"1371_CR59","doi-asserted-by":"crossref","unstructured":"Meng, F. et al. Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation. Mol. Neurodegener 6, 34 (2011).","DOI":"10.1186\/1750-1326-6-34"},{"key":"1371_CR60","doi-asserted-by":"crossref","unstructured":"Jiang, H. et al. Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat. Commun. 3, 668 (2012).","DOI":"10.1038\/ncomms1669"},{"key":"1371_CR61","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s13024-020-00367-7","volume":"15","author":"P Ge","year":"2020","unstructured":"Ge, P., Dawson, V. L. & Dawson, T. M. PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson\u2019s disease. Mol. Neurodegener. 15, 20 (2020).","journal-title":"Mol. Neurodegener."},{"key":"1371_CR62","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1016\/j.joca.2021.01.002","volume":"29","author":"J Lin","year":"2021","unstructured":"Lin, J. et al. Inhibition of LRRK2 restores parkin-mediated mitophagy and attenuates intervertebral disc degeneration. Osteoarthr. Cartil. 29, 579\u2013591 (2021).","journal-title":"Osteoarthr. Cartil."},{"key":"1371_CR63","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s41531-023-00491-3","volume":"9","author":"BA Killinger","year":"2023","unstructured":"Killinger, B. A. et al. Distribution of phosphorylated alpha-synuclein in non-diseased brain implicates olfactory bulb mitral cells in synucleinopathy pathogenesis. NPJ Parkinsons Dis. 9, 43 (2023).","journal-title":"NPJ Parkinsons Dis."},{"key":"1371_CR64","doi-asserted-by":"crossref","unstructured":"Darricau, M. et al. Tau seeds from patients induce progressive supranuclear palsy pathology and symptoms in primates. Brain 146, 2524\u20132534 (2023).","DOI":"10.1093\/brain\/awac428"},{"key":"1371_CR65","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1042\/BST20180025","volume":"46","author":"T Briston","year":"2018","unstructured":"Briston, T. & Hicks, A. R. Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention. Biochem Soc. Trans. 46, 829\u2013842 (2018).","journal-title":"Biochem Soc. Trans."},{"key":"1371_CR66","doi-asserted-by":"crossref","unstructured":"Khandelwal, P. J. et al. Parkinson-related parkin reduces \u03b1-Synuclein phosphorylation in a gene transfer model. Mol. Neurodegener 5, 47 (2010).","DOI":"10.1186\/1750-1326-5-47"},{"key":"1371_CR67","doi-asserted-by":"publisher","first-page":"2230","DOI":"10.3390\/biomedicines11082230","volume":"11","author":"AG Bispo","year":"2023","unstructured":"Bispo, A. G. et al. Investigation of PRKN Mutations in Levodopa-Induced Dyskinesia in Parkinson\u2019s Disease Treatment. Biomedicines 11, 2230 (2023).","journal-title":"Biomedicines"},{"key":"1371_CR68","doi-asserted-by":"crossref","unstructured":"Sassone, J., Valtorta, F. & Ciammola, A. Early Dyskinesias in Parkinson\u2019s Disease Patients With Parkin Mutation: A Primary Corticostriatal Synaptopathy? Front. Neurosci. 13, 273 (2019).","DOI":"10.3389\/fnins.2019.00273"},{"key":"1371_CR69","first-page":"S70","volume":"47","author":"F Calon","year":"2000","unstructured":"Calon, F. et al. Molecular basis of levodopa-induced dyskinesias. Ann. Neurol. 47, S70\u20138 (2000).","journal-title":"Ann. Neurol."},{"key":"1371_CR70","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/nrn2471","volume":"9","author":"P Jenner","year":"2008","unstructured":"Jenner, P. Molecular mechanisms of L-DOPA-induced dyskinesia. Nat. Rev. Neurosci. 9, 665\u2013677 (2008).","journal-title":"Nat. Rev. Neurosci."},{"key":"1371_CR71","doi-asserted-by":"crossref","unstructured":"Tatkiewicz, W. et al. Methods for characterization of protein aggregates. Methods Mol. Biol. 1258, 387\u2013401 (2015).","DOI":"10.1007\/978-1-4939-2205-5_22"},{"key":"1371_CR72","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1017\/cjn.2015.13","volume":"42","author":"AH Rajput","year":"2015","unstructured":"Rajput, A. H. & Rajput, A. Saskatchewan movement disorders program. Can. J. Neurol. Sci. 42, 74\u201387 (2015).","journal-title":"Can. J. Neurol. Sci."},{"key":"1371_CR73","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1002\/mds.10031","volume":"17","author":"AH Rajput","year":"2002","unstructured":"Rajput, A. H. et al. Clinical-pathological study of levodopa complications. Mov. Disord. 17, 289\u2013296 (2002).","journal-title":"Mov. Disord."},{"key":"1371_CR74","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1002\/mdc3.12476","volume":"4","author":"M Skorvanek","year":"2017","unstructured":"Skorvanek, M. et al. Differences in MDS-UPDRS Scores Based on Hoehn and Yahr Stage and Disease Duration. Mov. Disord. Clin. Pr. 4, 536\u2013544 (2017).","journal-title":"Mov. Disord. Clin. Pr."},{"key":"1371_CR75","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13293-025-00692-w","volume":"16","author":"SL Schaffner","year":"2025","unstructured":"Schaffner, S. L., Tosefsky, K. N., Inskter, A. M., Appel-Cresswell, S. & Schulze-Hentrich, J. M. Sex and gender differences in the molecular etiology of Parkinson\u2019s disease: considerations for study design and data analysis. Biol. Sex. Differ. 16, 7 (2025).","journal-title":"Biol. Sex. Differ."},{"key":"1371_CR76","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1093\/brain\/awr301","volume":"135","author":"S Paris-Robidas","year":"2012","unstructured":"Paris-Robidas, S. et al. Defective dentate nucleus GABA receptors in essential tremor. Brain 135, 105\u2013116 (2012).","journal-title":"Brain"},{"key":"1371_CR77","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/0169-328X(94)00219-5","volume":"28","author":"AE Kingsbury","year":"1995","unstructured":"Kingsbury, A. E. et al. Tissue pH as an indicator of mRNA preservation in human post-mortem brain. Mol. Brain Res. 28, 311\u2013318 (1995).","journal-title":"Mol. Brain Res."},{"key":"1371_CR78","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1093\/jnen\/nlw109","volume":"76","author":"C Tremblay","year":"2017","unstructured":"Tremblay, C. et al. Association of Neuropathological Markers in the Parietal Cortex With Antemortem Cognitive Function in Persons With Mild Cognitive Impairment and Alzheimer Disease. J. Neuropathol. Exp. Neurol. 76, 70\u201388 (2017).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"1371_CR79","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1097\/NEN.0b013e31822c62cf","volume":"70","author":"C Tremblay","year":"2011","unstructured":"Tremblay, C., St-Amour, I., Schneider, J., Bennett, D. A. & Calon, F. Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease. J. Neuropathol. Exp. Neurol. 70, 788\u2013798 (2011).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"1371_CR80","doi-asserted-by":"publisher","first-page":"574","DOI":"10.4103\/NRR.NRR-D-23-00595","volume":"20","author":"O Kerdiles","year":"2025","unstructured":"Kerdiles, O. et al. Additive neurorestorative effects of exercise and docosahexaenoic acid intake in a mouse model of Parkinson\u2019s disease. Neural Regen. Res. 20, 574\u2013586 (2025).","journal-title":"Neural Regen. Res."}],"container-title":["npj Parkinson's Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41531-026-01371-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41531-026-01371-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41531-026-01371-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T08:02:18Z","timestamp":1780041738000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41531-026-01371-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":80,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1371"],"URL":"https:\/\/doi.org\/10.1038\/s41531-026-01371-2","relation":{},"ISSN":["2373-8057"],"issn-type":[{"value":"2373-8057","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]},"assertion":[{"value":"12 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2026","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":"128"}}