{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:48:27Z","timestamp":1792784907655,"version":"4.5.0"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"HFSP Long-term Fellowship","award":["LT000559\/2021-L"],"award-info":[{"award-number":["LT000559\/2021-L"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB1286"],"award-info":[{"award-number":["SFB1286"]}],"id":[{"id":"10.13039\/501100001659","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>Alpha-synuclein (aSyn) is an intrinsically disordered protein involved in phase separation and several age-associated neurodegenerative disorders, including Parkinson\u2019s disease. However, its function and pathological role remain elusive. Here, we modeled different aSyn assemblies in living cells by exploiting its interaction with synphilin-1 (Sph1). We developed a model that reports on gel- and solid-like inclusions through coexpression of aSyn and Sph1. Distinct morphological differences emerged between VN-aSyn + aSyn-VC and VN-Sph1 + aSyn-VC assemblies, showing unique antibody recognition, proteinase K resistance, and protein mobilities. The VN-Sph1 + aSyn-VC interaction could be manipulated to alter inclusion size and number. These inclusions also contained lysosomes and AP-1 vesicles, aligning with observations in human brain tissue. Our study offers new insight into aSyn aggregation and release, highlighting the importance of Sph1 and other aSyn-interacting proteins in synucleinopathies, which involve diverse copathologies only now beginning to be understood.<\/jats:p>","DOI":"10.1038\/s41531-025-01144-3","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T12:05:25Z","timestamp":1763640325000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Synphilin-1 modulates alpha-synuclein assembly, release and uptake"],"prefix":"10.1038","volume":"11","author":[{"given":"Diana F.","family":"L\u00e1zaro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Triana","family":"Amen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Gerhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyuan","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Kruse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia I.","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragomir","family":"Milovanovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter","family":"H\u00f6glinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brit","family":"Mollenhauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin C.","family":"Luk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia MY-","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago F.","family":"Outeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"1144_CR1","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/8820","volume":"22","author":"S Engelender","year":"1999","unstructured":"Engelender, S. et al. Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat. Genet. 22, 110\u2013114 (1999).","journal-title":"Nat. Genet."},{"key":"1144_CR2","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1046\/j.1471-4159.2001.00301.x","volume":"77","author":"H Kawamata","year":"2001","unstructured":"Kawamata, H. et al. Interaction of alpha-synuclein and synphilin-1: effect of Parkinson\u2019s disease-associated mutations. J. Neurochem. 77, 929\u2013934 (2001).","journal-title":"J. Neurochem."},{"key":"1144_CR3","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/S1474-4422(24)00176-5","volume":"23","author":"M Goedert","year":"2024","unstructured":"Goedert, M. et al. Abandon the NAC in alpha-synuclein. Lancet Neurol. 23, 669 (2024).","journal-title":"Lancet Neurol."},{"key":"1144_CR4","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1038\/nm1001-1144","volume":"7","author":"KK Chung","year":"2001","unstructured":"Chung, K. K. et al. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat. Med. 7, 1144\u20131150 (2001).","journal-title":"Nat. Med."},{"key":"1144_CR5","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1007\/s003350010123","volume":"11","author":"S Engelender","year":"2000","unstructured":"Engelender, S. et al. Organization of the human synphilin-1 gene, a candidate for Parkinson\u2019s disease. Mamm. Genome 11, 763\u2013766 (2000).","journal-title":"Mamm. Genome"},{"key":"1144_CR6","doi-asserted-by":"publisher","first-page":"23927","DOI":"10.1074\/jbc.M201115200","volume":"277","author":"CS Ribeiro","year":"2002","unstructured":"Ribeiro, C. S. et al. Synphilin-1 is developmentally localized to synaptic terminals, and its association with synaptic vesicles is modulated by alpha-synuclein. J. Biol. Chem. 277, 23927\u201323933 (2002).","journal-title":"J. Biol. Chem."},{"key":"1144_CR7","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1007\/s00401-002-0629-2","volume":"105","author":"IJ Murray","year":"2003","unstructured":"Murray, I. J. et al. Synphilin in normal human brains and in synucleinopathies: studies with new antibodies. Acta Neuropathol. 105, 177\u2013184 (2003).","journal-title":"Acta Neuropathol."},{"key":"1144_CR8","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1002\/1531-8249(200004)47:4<521::AID-ANA18>3.0.CO;2-B","volume":"47","author":"K Wakabayashi","year":"2000","unstructured":"Wakabayashi, K. et al. Synphilin-1 is present in Lewy bodies in Parkinson\u2019s disease. Ann. Neurol. 47, 521\u2013523 (2000).","journal-title":"Ann. Neurol."},{"key":"1144_CR9","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1111\/jnc.13392","volume":"136","author":"T Brudek","year":"2016","unstructured":"Brudek, T. et al. Altered alpha-synuclein, parkin, and synphilin isoform levels in multiple system atrophy brains. J. Neurochem. 136, 172\u2013185 (2016).","journal-title":"J. Neurochem."},{"key":"1144_CR10","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1093\/hmg\/ddq086","volume":"19","author":"WW Smith","year":"2010","unstructured":"Smith, W. W. et al. Synphilin-1 attenuates neuronal degeneration in the A53T alpha-synuclein transgenic mouse model. Hum. Mol. Genet. 19, 2087\u20132098 (2010).","journal-title":"Hum. Mol. Genet."},{"key":"1144_CR11","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1096\/fj.09-133082","volume":"24","author":"YY Xie","year":"2010","unstructured":"Xie, Y. Y. et al. Interaction with synphilin-1 promotes inclusion formation of alpha-synuclein: mechanistic insights and pathological implication. FASEB J. 24, 196\u2013205 (2010).","journal-title":"FASEB J."},{"key":"1144_CR12","doi-asserted-by":"publisher","first-page":"29106","DOI":"10.1074\/jbc.M302763200","volume":"278","author":"T Ito","year":"2003","unstructured":"Ito, T. et al. Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1. J. Biol. Chem. 278, 29106\u201329114 (2003).","journal-title":"J. Biol. Chem."},{"key":"1144_CR13","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.nbd.2005.03.021","volume":"20","author":"R Bandopadhyay","year":"2005","unstructured":"Bandopadhyay, R. et al. Synphilin-1 and parkin show overlapping expression patterns in human brain and form aggresomes in response to proteasomal inhibition. Neurobiol. Dis. 20, 401\u2013411 (2005).","journal-title":"Neurobiol. Dis."},{"key":"1144_CR14","doi-asserted-by":"publisher","first-page":"51504","DOI":"10.1074\/jbc.M306347200","volume":"278","author":"Y Nagano","year":"2003","unstructured":"Nagano, Y. et al. Siah-1 facilitates ubiquitination and degradation of synphilin-1. J. Biol. Chem. 278, 51504\u201351514 (2003).","journal-title":"J. Biol. Chem."},{"key":"1144_CR15","doi-asserted-by":"publisher","first-page":"5500","DOI":"10.1073\/pnas.0401081101","volume":"101","author":"E Liani","year":"2004","unstructured":"Liani, E. et al. Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson\u2019s disease. Proc. Natl. Acad. Sci. USA 101, 5500\u20135505 (2004).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"1144_CR16","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1093\/hmg\/ddv504","volume":"25","author":"J Liu","year":"2016","unstructured":"Liu, J. et al. Synphilin-1 attenuates mutant LRRK2-induced neurodegeneration in Parkinson\u2019s disease models. Hum. Mol. Genet. 25, 672\u2013680 (2016).","journal-title":"Hum. Mol. Genet."},{"key":"1144_CR17","doi-asserted-by":"publisher","first-page":"3476","DOI":"10.1093\/hmg\/ddw189","volume":"25","author":"R Szargel","year":"2016","unstructured":"Szargel, R. et al. The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway. Hum. Mol. Genet. 25, 3476\u20133490 (2016).","journal-title":"Hum. Mol. Genet."},{"key":"1144_CR18","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","volume":"276","author":"MH Polymeropoulos","year":"1997","unstructured":"Polymeropoulos, M. H. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson\u2019s disease. Science 276, 2045\u20132047 (1997).","journal-title":"Science"},{"key":"1144_CR19","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/42166","volume":"388","author":"MG Spillantini","year":"1997","unstructured":"Spillantini, M. G. et al. Alpha-synuclein in Lewy bodies. Nature 388, 839\u2013840 (1997).","journal-title":"Nature"},{"key":"1144_CR20","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":"1144_CR21","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1002\/ana.10846","volume":"55","author":"M Farrer","year":"2004","unstructured":"Farrer, M. et al. Comparison of kindreds with Parkinsonism and alpha-synuclein genomic multiplications. Ann. Neurol. 55, 174\u2013179 (2004).","journal-title":"Ann. Neurol."},{"key":"1144_CR22","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1007\/PL00000671","volume":"57","author":"CB Lucking","year":"2000","unstructured":"Lucking, C. B. and A. Brice, Alpha-synuclein and Parkinson\u2019s disease. Cell Mol. Life Sci. 57, 1894\u20131908 (2000).","journal-title":"Cell Mol. Life Sci."},{"key":"1144_CR23","doi-asserted-by":"publisher","first-page":"2804","DOI":"10.1523\/JNEUROSCI.08-08-02804.1988","volume":"8","author":"L Maroteaux","year":"1988","unstructured":"Maroteaux, L., Campanelli, J. T. & Scheller, R. H. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci. 8, 2804\u20132815 (1988).","journal-title":"J. Neurosci."},{"key":"1144_CR24","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1093\/hmg\/ddy326","volume":"28","author":"R Pinho","year":"2019","unstructured":"Pinho, R. et al. Nuclear localization and phosphorylation modulate pathological effects of alpha-synuclein. Hum. Mol. Genet. 28, 31\u201350 (2019).","journal-title":"Hum. Mol. Genet."},{"key":"1144_CR25","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1126\/science.1195227","volume":"329","author":"J Burre","year":"2010","unstructured":"Burre, J. et al. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329, 1663\u20131667 (2010).","journal-title":"Science"},{"key":"1144_CR26","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1016\/S1474-4422(11)70213-7","volume":"10","author":"K Vekrellis","year":"2011","unstructured":"Vekrellis, K. et al. Pathological roles of alpha-synuclein in neurological disorders. Lancet Neurol. 10, 1015\u20131025 (2011).","journal-title":"Lancet Neurol."},{"key":"1144_CR27","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/S0896-6273(00)80886-7","volume":"25","author":"A Abeliovich","year":"2000","unstructured":"Abeliovich, A. et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239\u2013252 (2000).","journal-title":"Neuron"},{"key":"1144_CR28","doi-asserted-by":"publisher","first-page":"49071","DOI":"10.1074\/jbc.M208046200","volume":"277","author":"M Hasegawa","year":"2002","unstructured":"Hasegawa, M. et al. Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. J. Biol. Chem. 277, 49071\u201349076 (2002).","journal-title":"J. Biol. Chem."},{"key":"1144_CR29","doi-asserted-by":"publisher","first-page":"29739","DOI":"10.1074\/jbc.M600933200","volume":"281","author":"JP Anderson","year":"2006","unstructured":"Anderson, J. P. et al. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. 281, 29739\u201329752 (2006).","journal-title":"J. Biol. Chem."},{"key":"1144_CR30","doi-asserted-by":"publisher","first-page":"3184","DOI":"10.1523\/JNEUROSCI.5922-09.2010","volume":"30","author":"KE Paleologou","year":"2010","unstructured":"Paleologou, K. E. et al. Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J. Neurosci. 30, 3184\u20133198 (2010).","journal-title":"J. Neurosci."},{"key":"1144_CR31","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1093\/brain\/awx056","volume":"140","author":"H Vicente Miranda","year":"2017","unstructured":"Vicente Miranda, H. et al. Glycation potentiates alpha-synuclein-associated neurodegeneration in synucleinopathies. Brain 140, 1399\u20131419 (2017).","journal-title":"Brain"},{"key":"1144_CR32","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.tox.2005.07.010","volume":"216","author":"Y Hirata","year":"2005","unstructured":"Hirata, Y. & Nagatsu, T. Rotenone and CCCP inhibit tyrosine hydroxylation in rat striatal tissue slices. Toxicology 216, 9\u201314 (2005).","journal-title":"Toxicology"},{"key":"1144_CR33","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.jns.2011.06.048","volume":"310","author":"EM Szego","year":"2011","unstructured":"Szego, E. M. et al. Dopamine-depletion and increased alpha-synuclein load induce degeneration of cortical cholinergic fibers in mice. J. Neurol. Sci. 310, 90\u201395 (2011).","journal-title":"J. Neurol. Sci."},{"key":"1144_CR34","doi-asserted-by":"publisher","first-page":"14524","DOI":"10.1073\/pnas.172514599","volume":"99","author":"W Dauer","year":"2002","unstructured":"Dauer, W. et al. Resistance of alpha -synuclein null mice to the Parkinsonian neurotoxin MPTP. Proc. Natl. Acad. Sci. USA 99, 14524\u201314529 (2002).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"1144_CR35","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1084\/jem.20160368","volume":"213","author":"NL Rey","year":"2016","unstructured":"Rey, N. L. et al. Widespread transneuronal propagation of alpha-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson\u2019s disease. J. Exp. Med. 213, 1759\u20131778 (2016).","journal-title":"J. Exp. Med."},{"key":"1144_CR36","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1126\/science.1227157","volume":"338","author":"KC Luk","year":"2012","unstructured":"Luk, K. C. et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949\u2013953 (2012).","journal-title":"Science"},{"key":"1144_CR37","doi-asserted-by":"publisher","first-page":"34885","DOI":"10.1074\/jbc.M110.148460","volume":"285","author":"T Nonaka","year":"2010","unstructured":"Nonaka, T. et al. Seeded aggregation and toxicity of {alpha}-synuclein and tau: cellular models of neurodegenerative diseases. J. Biol. Chem. 285, 34885\u201334898 (2010).","journal-title":"J. Biol. Chem."},{"key":"1144_CR38","doi-asserted-by":"publisher","first-page":"e1867","DOI":"10.1371\/journal.pone.0001867","volume":"3","author":"TF Outeiro","year":"2008","unstructured":"Outeiro, T. F. et al. Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS One 3, e1867 (2008).","journal-title":"PLoS One"},{"key":"1144_CR39","doi-asserted-by":"publisher","first-page":"e1004741","DOI":"10.1371\/journal.pgen.1004741","volume":"10","author":"DF Lazaro","year":"2014","unstructured":"Lazaro, D. F. et al. Systematic comparison of the effects of alpha-synuclein mutations on its oligomerization and aggregation. PLoS Genet. 10, e1004741 (2014).","journal-title":"PLoS Genet."},{"key":"1144_CR40","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/s00401-006-0114-4","volume":"112","author":"Y Fujita","year":"2006","unstructured":"Fujita, Y. et al. Fragmentation of Golgi apparatus of nigral neurons with alpha-synuclein-positive inclusions in patients with Parkinson\u2019s disease. Acta Neuropathol. 112, 261\u2013265 (2006).","journal-title":"Acta Neuropathol."},{"key":"1144_CR41","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1002\/iub.1054","volume":"64","author":"D Corda","year":"2012","unstructured":"Corda, D. et al. Golgi complex fragmentation in G2\/M transition: an organelle-based cell-cycle checkpoint. IUBMB Life 64, 661\u2013670 (2012).","journal-title":"IUBMB Life"},{"key":"1144_CR42","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1073\/pnas.1220978110","volume":"110","author":"DA Thayer","year":"2013","unstructured":"Thayer, D. A., Jan, Y. N. & Jan, L. Y. Increased neuronal activity fragments the Golgi complex. Proc. Natl. Acad. Sci. USA 110, 1482\u20131487 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"1144_CR43","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.nbd.2007.08.015","volume":"29","author":"S Nakagomi","year":"2008","unstructured":"Nakagomi, S. et al. A Golgi fragmentation pathway in neurodegeneration. Neurobiol. Dis. 29, 221\u2013231 (2008).","journal-title":"Neurobiol. Dis."},{"key":"1144_CR44","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/s40478-016-0402-8","volume":"4","author":"DF Lazaro","year":"2016","unstructured":"Lazaro, D. F. et al. The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation. Acta Neuropathol. Commun. 4, 128 (2016).","journal-title":"Acta Neuropathol. Commun."},{"key":"1144_CR45","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.nbd.2018.08.001","volume":"119","author":"I Paiva","year":"2018","unstructured":"Paiva, I. et al. Alpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function. Neurobiol. Dis. 119, 121\u2013135 (2018).","journal-title":"Neurobiol. Dis."},{"key":"1144_CR46","doi-asserted-by":"publisher","first-page":"2465","DOI":"10.1038\/sj.emboj.7601686","volume":"26","author":"A Colanzi","year":"2007","unstructured":"Colanzi, A. et al. The Golgi mitotic checkpoint is controlled by BARS-dependent fission of the Golgi ribbon into separate stacks in G2. EMBO J. 26, 2465\u20132476 (2007).","journal-title":"EMBO J."},{"key":"1144_CR47","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-69744-y","volume":"10","author":"A Dominguez-Meijide","year":"2020","unstructured":"Dominguez-Meijide, A. et al. Effects of pharmacological modulators of alpha-synuclein and tau aggregation and internalization. Sci. Rep. 10, 12827 (2020).","journal-title":"Sci. Rep."},{"key":"1144_CR48","doi-asserted-by":"publisher","first-page":"2116","DOI":"10.1096\/fj.201800148RRR","volume":"33","author":"V Prasad","year":"2019","unstructured":"Prasad, V. et al. Monitoring alpha-synuclein multimerization in vivo. FASEB J. 33, 2116\u20132131 (2019).","journal-title":"FASEB J."},{"key":"1144_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.307","volume":"5","author":"L Zondler","year":"2014","unstructured":"Zondler, L. et al. DJ-1 interactions with alpha-synuclein attenuate aggregation and cellular toxicity in models of Parkinson\u2019s disease. Cell Death Dis. 5, e1350 (2014).","journal-title":"Cell Death Dis."},{"key":"1144_CR50","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.febslet.2011.11.019","volume":"586","author":"F Herrera","year":"2012","unstructured":"Herrera, F. & Outeiro, T. F. alpha-Synuclein modifies huntingtin aggregation in living cells. FEBS Lett. 586, 7\u201312 (2012).","journal-title":"FEBS Lett."},{"key":"1144_CR51","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1016\/j.bbadis.2015.05.002","volume":"1852","author":"K Eckermann","year":"2015","unstructured":"Eckermann, K., Kugler, S. & Bahr, M. Dimerization propensities of Synucleins are not predictive for Synuclein aggregation. Biochim. Biophys. Acta 1852, 1658\u20131664 (2015).","journal-title":"Biochim. Biophys. Acta"},{"key":"1144_CR52","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.tibs.2020.12.005","volume":"46","author":"B Portz","year":"2021","unstructured":"Portz, B., Lee, B. L. & Shorter, J. FUS and TDP-43 phases in health and disease. Trends Biochem Sci. 46, 550\u2013563 (2021).","journal-title":"Trends Biochem Sci."},{"key":"1144_CR53","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1038\/s41557-020-0465-9","volume":"12","author":"S Ray","year":"2020","unstructured":"Ray, S. et al. alpha-Synuclein aggregation nucleates through liquid-liquid phase separation. Nat. Chem. 12, 705\u2013716 (2020).","journal-title":"Nat. Chem."},{"key":"1144_CR54","doi-asserted-by":"publisher","first-page":"R1097","DOI":"10.1016\/j.cub.2017.08.069","volume":"27","author":"S Alberti","year":"2017","unstructured":"Alberti, S. Phase separation in biology. Curr. Biol. 27, R1097\u2013R1102 (2017).","journal-title":"Curr. Biol."},{"key":"1144_CR55","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1038\/s41593-019-0423-2","volume":"22","author":"SH Shahmoradian","year":"2019","unstructured":"Shahmoradian, S. H. et al. Lewy pathology in Parkinson\u2019s disease consists of crowded organelles and lipid membranes. Nat. Neurosci. 22, 1099\u20131109 (2019).","journal-title":"Nat. Neurosci."},{"key":"1144_CR56","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22108-0","volume":"12","author":"VA Trinkaus","year":"2021","unstructured":"Trinkaus, V. A. et al. In situ architecture of neuronal alpha-Synuclein inclusions. Nat. Commun. 12, 2110 (2021).","journal-title":"Nat. Commun."},{"key":"1144_CR57","doi-asserted-by":"publisher","first-page":"166961","DOI":"10.1016\/j.jmb.2021.166961","volume":"433","author":"C Hoffmann","year":"2021","unstructured":"Hoffmann, C. et al. Synapsin Condensates Recruit alpha-Synuclein. J. Mol. Biol. 433, 166961 (2021).","journal-title":"J. Mol. Biol."},{"key":"1144_CR58","doi-asserted-by":"publisher","first-page":"ar10","DOI":"10.1091\/mbc.E23-07-0269","volume":"35","author":"JN Wallace","year":"2024","unstructured":"Wallace, J. N. et al. Excess phosphoserine-129 alpha-synuclein induces synaptic vesicle trafficking and declustering defects at a vertebrate synapse. Mol. Biol. Cell 35, ar10 (2024).","journal-title":"Mol. Biol. Cell"},{"key":"1144_CR59","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1126\/science.1067389","volume":"295","author":"PK Auluck","year":"2002","unstructured":"Auluck, P. K. et al. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson\u2019s disease. Science 295, 865\u2013868 (2002).","journal-title":"Science"},{"key":"1144_CR60","doi-asserted-by":"publisher","first-page":"25497","DOI":"10.1074\/jbc.M400255200","volume":"279","author":"J Klucken","year":"2004","unstructured":"Klucken, J. et al. Hsp70 reduces alpha-synuclein aggregation and toxicity. J. Biol. Chem. 279, 25497\u201325502 (2004).","journal-title":"J. Biol. Chem."},{"key":"1144_CR61","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.bbrc.2006.10.085","volume":"351","author":"TF Outeiro","year":"2006","unstructured":"Outeiro, T. F. et al. Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation. Biochem Biophys. Res. Commun. 351, 631\u2013638 (2006).","journal-title":"Biochem Biophys. Res. Commun."},{"key":"1144_CR62","doi-asserted-by":"publisher","first-page":"RRN1210","DOI":"10.1371\/currents.RRN1210","volume":"3","author":"F Herrera","year":"2011","unstructured":"Herrera, F. et al. Visualization of cell-to-cell transmission of mutant huntingtin oligomers. PLoS Curr. 3, RRN1210 (2011).","journal-title":"PLoS Curr."},{"key":"1144_CR63","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/S0306-4522(01)00113-0","volume":"104","author":"PJ McLean","year":"2001","unstructured":"McLean, P. J., Kawamata, H. & Hyman, B. T. Alpha-synuclein-enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons. Neuroscience 104, 901\u2013912 (2001).","journal-title":"Neuroscience"},{"key":"1144_CR64","first-page":"282","volume":"13","author":"MC Hardenberg","year":"2021","unstructured":"Hardenberg, M. C. et al. Observation of an alpha-synuclein liquid droplet state and its maturation into Lewy body-like assemblies. J. Mol. Cell Biol. 13, 282\u2013294 (2021).","journal-title":"J. Mol. Cell Biol."},{"key":"1144_CR65","doi-asserted-by":"crossref","unstructured":"Wegmann, S., et al., Tau protein liquid-liquid phase separation can initiate tau aggregation. Embo J., 37, e98049 (2018).","DOI":"10.15252\/embj.201798049"},{"key":"1144_CR66","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1016\/j.str.2016.07.007","volume":"24","author":"AE Conicella","year":"2016","unstructured":"Conicella, A. E. et al. ALS mutations disrupt phase separation mediated by alpha-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24, 1537\u20131549 (2016).","journal-title":"Structure"},{"key":"1144_CR67","doi-asserted-by":"publisher","first-page":"6306","DOI":"10.1074\/jbc.RA118.007222","volume":"294","author":"WM Babinchak","year":"2019","unstructured":"Babinchak, W. M. et al. The role of liquid-liquid phase separation in aggregation of the TDP-43 low-complexity domain. J. Biol. Chem. 294, 6306\u20136317 (2019).","journal-title":"J. Biol. Chem."},{"key":"1144_CR68","doi-asserted-by":"publisher","DOI":"10.1038\/srep13416","volume":"5","author":"NE Farrawell","year":"2015","unstructured":"Farrawell, N. E. et al. Distinct partitioning of ALS associated TDP-43, FUS and SOD1 mutants into cellular inclusions. Sci. Rep. 5, 13416 (2015).","journal-title":"Sci. Rep."},{"key":"1144_CR69","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/S1474-4422(10)70195-2","volume":"9","author":"IR Mackenzie","year":"2010","unstructured":"Mackenzie, I. R., Rademakers, R. & Neumann, M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9, 995\u20131007 (2010).","journal-title":"Lancet Neurol."},{"key":"1144_CR70","doi-asserted-by":"publisher","first-page":"5221","DOI":"10.1523\/JNEUROSCI.4650-14.2015","volume":"35","author":"J Burre","year":"2015","unstructured":"Burre, J., Sharma, M. & Sudhof, T. C. Definition of a molecular pathway mediating alpha-synuclein neurotoxicity. J. Neurosci. 35, 5221\u20135232 (2015).","journal-title":"J. Neurosci."},{"key":"1144_CR71","doi-asserted-by":"publisher","first-page":"2432","DOI":"10.1093\/hmg\/dds058","volume":"21","author":"V Sancenon","year":"2012","unstructured":"Sancenon, V. et al. Suppression of alpha-synuclein toxicity and vesicle trafficking defects by phosphorylation at S129 in yeast depends on genetic context. Hum. Mol. Genet. 21, 2432\u20132449 (2012).","journal-title":"Hum. Mol. Genet."},{"key":"1144_CR72","doi-asserted-by":"publisher","first-page":"106010","DOI":"10.1016\/j.nbd.2023.106010","volume":"178","author":"S Lin","year":"2023","unstructured":"Lin, S. et al. Overexpression of alpha synuclein disrupts APP and endolysosomal axonal trafficking in a mouse model of synucleinopathy. Neurobiol. Dis. 178, 106010 (2023).","journal-title":"Neurobiol. Dis."},{"key":"1144_CR73","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/978-3-030-38266-7_9","volume":"1233","author":"DF Lazaro","year":"2020","unstructured":"Lazaro, D. F. & Outeiro, T. F. The interplay between proteostasis systems and Parkinson\u2019s disease. Adv. Exp. Med Biol. 1233, 223\u2013236 (2020).","journal-title":"Adv. Exp. Med Biol."},{"key":"1144_CR74","doi-asserted-by":"crossref","unstructured":"Dashtipour, K. et al., Hypermethylation of synphilin-1, alpha-synuclein-interacting protein (SNCAIP) gene in the cerebral cortex of patients with sporadic Parkinson\u2019s disease. Brain Sci., 7, 74 (2017).","DOI":"10.3390\/brainsci7070074"},{"key":"1144_CR75","first-page":"239","volume":"6","author":"L Tonges","year":"2014","unstructured":"Tonges, L. et al. Alpha-synuclein mutations impair axonal regeneration in models of Parkinson\u2019s disease. Front. Aging Neurosci. 6, 239 (2014).","journal-title":"Front. Aging Neurosci."},{"key":"1144_CR76","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.neuron.2011.08.033","volume":"72","author":"LA Volpicelli-Daley","year":"2011","unstructured":"Volpicelli-Daley, L. A. et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57\u201371 (2011).","journal-title":"Neuron"},{"key":"1144_CR77","doi-asserted-by":"publisher","first-page":"754","DOI":"10.4161\/auto.19371","volume":"8","author":"J Klucken","year":"2012","unstructured":"Klucken, J. et al. Alpha-synuclein aggregation involves a bafilomycin A 1-sensitive autophagy pathway. Autophagy 8, 754\u2013766 (2012).","journal-title":"Autophagy"},{"key":"1144_CR78","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/s40478-021-01175-w","volume":"9","author":"C Bargar","year":"2021","unstructured":"Bargar, C. et al. Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson\u2019s disease and dementia with Lewy bodies. Acta Neuropathol. Commun. 9, 62 (2021).","journal-title":"Acta Neuropathol. Commun."},{"key":"1144_CR79","doi-asserted-by":"publisher","first-page":"20051","DOI":"10.1073\/pnas.0908005106","volume":"106","author":"KC Luk","year":"2009","unstructured":"Luk, K. C. et al. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Natl. Acad. Sci. USA 106, 20051\u201320056 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["npj Parkinson's Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41531-025-01144-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41531-025-01144-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41531-025-01144-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T13:05:36Z","timestamp":1763643936000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41531-025-01144-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":79,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1144"],"URL":"https:\/\/doi.org\/10.1038\/s41531-025-01144-3","relation":{},"ISSN":["2373-8057"],"issn-type":[{"value":"2373-8057","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,20]]},"assertion":[{"value":"3 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2025","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":"326"}}