{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T03:45:30Z","timestamp":1780717530806,"version":"3.54.1"},"reference-count":41,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,28]],"date-time":"2025-06-28T00:00:00Z","timestamp":1751068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01NS086074-05"],"award-info":[{"award-number":["1R01NS086074-05"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01NS092093-05"],"award-info":[{"award-number":["1R01NS092093-05"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018231","name":"Aligning Science Across Parkinson's","doi-asserted-by":"publisher","award":["ASAP-024407"],"award-info":[{"award-number":["ASAP-024407"]}],"id":[{"id":"10.13039\/100018231","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pathological aggregation of \u03b1-synuclein (\u03b1S) is implicated in the pathogenesis of Parkinson\u2019s disease (PD) and other \u03b1-synucleinopathies. The current view is that neuron-to-neuron spreading of \u03b1S pathology contributes to the progression of \u03b1-synucleinopathy. We used an A53T mutant human \u03b1S transgenic mouse model (TgA53T) to examine whether the site of pathogenic \u03b1S inoculation affects the pattern of neuropathology and whether soluble and insoluble fractions derived from crude pathogenic tissue lysates exhibit differential capacities to initiate \u03b1S pathology. To test whether the inoculation site impacts the ultimate spatial\/temporal patterns of \u03b1S pathology, \u03b1S preformed fibrils (PFFs), or brain homogenates from TgA53T mice with \u03b1-synucleinopathy, were injected into the cortex\/striatum, brainstem, or skeletal muscle. In all cases, inoculation of pathogenic \u03b1S induced end-stage motor dysfunction within ~100 days post-inoculation (dpi). Significantly, irrespective of the inoculation sites, the ultimate distribution of the \u03b1S pathology was like that seen in normally aged TgA53T mice at end-stage, indicating that the intrinsic neuronal vulnerability is a significant determinant in the induction of \u03b1S pathology, even when initiated by inoculation of pathogenic \u03b1S. Temporal analysis of brainstem-injected TgA53T mice show that initial \u03b1S pathology was seen by 30 days post-inoculation and inflammatory changes occur at later stages. In addition, we show that both highly soluble (S150) and insoluble (P150) fractions from end-stage TgA53T mice can seed de novo \u03b1S pathology in vivo. Moreover, the endoplasmic reticulum (ER)-enriched fraction from the TgA53T mice were highly pathogenic as the ER fraction induced \u03b1S pathology faster than other fractions when injected unilaterally into TgA53T mice. Our results suggest that multiple \u03b1S species from the brain can initiate the development of progressive \u03b1S pathology.<\/jats:p>","DOI":"10.3390\/ijms26136254","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T05:28:28Z","timestamp":1751347708000},"page":"6254","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Soluble and Insoluble Lysates from the Human A53T Mutant \u03b1-Synuclein Transgenic Mouse Model Induces \u03b1-Synucleinopathy Independent of Injection Site"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9184-4160","authenticated-orcid":false,"given":"Justin","family":"Barnes","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott C.","family":"Vermilyea","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce","family":"Meints","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor","family":"Martell-Martinez","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5865-9682","authenticated-orcid":false,"given":"Michael K.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Emamzadeh, F.N., and Surguchov, A. (2018). Parkinson\u2019s Disease: Biomarkers, Treatment, and Risk Factors. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00612"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S58","DOI":"10.1038\/nm1068","article-title":"Genetic clues to the pathogenesis of Parkinson\u2019s disease","volume":"10","author":"Vila","year":"2004","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nm.2165","article-title":"Missing pieces in the Parkinson\u2019s disease puzzle","volume":"16","author":"Obeso","year":"2010","journal-title":"Nat. Med."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1111\/jnc.14779","article-title":"Spreading of alpha-synuclein\u2014Relevant or epiphenomenon?","volume":"150","author":"Killinger","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1093\/jnen\/61.5.413","article-title":"Where does parkinson disease pathology begin in the brain?","volume":"61","author":"Rub","year":"2002","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/nm1746","article-title":"Lewy bodies in grafted neurons in subjects with Parkinson\u2019s disease suggest host-to-graft disease propagation","volume":"14","author":"Li","year":"2008","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nm1747","article-title":"Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson\u2019s disease","volume":"14","author":"Kordower","year":"2008","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1084\/jem.20112457","article-title":"Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice","volume":"209","author":"Luk","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/s41593-019-0457-5","article-title":"Spread of alpha-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis","volume":"22","author":"Henderson","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"139","DOI":"10.14802\/jmd.19046","article-title":"Modeling alpha-Synuclein Propagation with Preformed Fibril Injections","volume":"12","author":"Chung","year":"2019","journal-title":"J. Mov. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10732","DOI":"10.1073\/pnas.1321785111","article-title":"Intramuscular injection of alpha-synuclein induces CNS alpha-synuclein pathology and a rapid-onset motor phenotype in transgenic mice","volume":"111","author":"Sacino","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"iii1","DOI":"10.1007\/s00415-002-1301-4","article-title":"Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson\u2019s disease (preclinical and clinical stages)","volume":"249","author":"Braak","year":"2002","journal-title":"J. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8968","DOI":"10.1073\/pnas.132197599","article-title":"Human alpha-synuclein-harboring familial Parkinson\u2019s disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice","volume":"99","author":"Lee","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s40035-022-00309-x","article-title":"Loss of tau expression attenuates neurodegeneration associated with alpha-synucleinopathy","volume":"11","author":"Vermilyea","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13024-020-00364-w","article-title":"alpha-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment","volume":"15","author":"Karim","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9754","DOI":"10.1523\/JNEUROSCI.0344-18.2018","article-title":"A53T mutant alpha-synuclein induces tau dependent postsynaptic impairment independent of neurodegenerative changes","volume":"38","author":"Teravskis","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3373","DOI":"10.1016\/j.celrep.2016.08.053","article-title":"Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity","volume":"16","author":"Luk","year":"2016","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0896-6273(01)00462-7","article-title":"beta-Synuclein inhibits alpha-synuclein aggregation: A possible role as an anti-parkinsonian factor","volume":"32","author":"Hashimoto","year":"2001","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Brown, J.W., Buell, A.K., Michaels, T.C., Meisl, G., Carozza, J., Flagmeier, P., Vendruscolo, M., Knowles, T.P., Dobson, C.M., and Galvagnion, C. (2016). beta-Synuclein suppresses both the initiation and amplification steps of alpha-synuclein aggregation via competitive binding to surfaces. Sci. Rep., 6.","DOI":"10.1038\/srep36010"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8748","DOI":"10.1038\/s41467-024-53086-8","article-title":"beta-synuclein regulates the phase transitions and amyloid conversion of alpha-synuclein","volume":"15","author":"Li","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"115761","DOI":"10.1016\/j.celrep.2025.115761","article-title":"beta-synuclein blocks alpha-synuclein condensate fusion to disrupt the maturation of phase separation","volume":"44","author":"Xu","year":"2025","journal-title":"Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13024-019-0335-3","article-title":"Microglia affect alpha-synuclein cell-to-cell transfer in a mouse model of Parkinson\u2019s disease","volume":"14","author":"George","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13024-017-0182-z","article-title":"Intrastriatal injection of alpha-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity","volume":"12","author":"Sorrentino","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-019-01977-2","article-title":"alpha-Synuclein and astrocytes: Tracing the pathways from homeostasis to neurodegeneration in Lewy body disease","volume":"138","author":"Sorrentino","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.nbd.2018.09.005","article-title":"Motor neuron loss and neuroinflammation in a model of alpha-synuclein-induced neurodegeneration","volume":"120","author":"Sorrentino","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12924","DOI":"10.1074\/jbc.M306390200","article-title":"Proteasomal inhibition by alpha-synuclein filaments and oligomers","volume":"279","author":"Lindersson","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/1750-1326-2-18","article-title":"Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers","volume":"2","author":"Kayed","year":"2007","journal-title":"Mol. Neurodegener."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3301","DOI":"10.1523\/JNEUROSCI.5368-11.2012","article-title":"Accumulation of Toxic alpha-Synuclein Oligomer within Endoplasmic Reticulum Occurs in alpha-Synucleinopathy In Vivo","volume":"32","author":"Colla","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3306","DOI":"10.1523\/JNEUROSCI.5367-11.2012","article-title":"Endoplasmic Reticulum Stress Is Important for the Manifestations of alpha-Synucleinopathy In Vivo","volume":"32","author":"Colla","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.nbd.2017.12.004","article-title":"Toxic properties of microsome-associated alpha-synuclein species in mouse primary neurons","volume":"111","author":"Colla","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41531-024-00640-2","article-title":"Microglial inhibition alleviates alpha-synuclein propagation and neurodegeneration in Parkinson\u2019s disease mouse model","volume":"10","author":"Kim","year":"2024","journal-title":"NPJ Park. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1073\/pnas.0406976102","article-title":"Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson\u2019s disease-linked mutations","volume":"102","author":"Li","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sonustun, B., Altay, M.F., Strand, C., Ebanks, K., Hondhamuni, G., Warner, T.T., Lashuel, H.A., and Bandopadhyay, R. (2022). Pathological Relevance of Post-Translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson\u2019s Disease and Multiple System Atrophy. Cells, 11.","DOI":"10.1101\/2022.01.11.475823"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/s41593-022-01239-7","article-title":"Post-translational modifications of soluble alpha-synuclein regulate the amplification of pathological alpha-synuclein","volume":"26","author":"Zhang","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00401-022-02425-4","article-title":"Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human alpha-synuclein transgenic mice","volume":"143","author":"Lloyd","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1093\/brain\/awad378","article-title":"Alzheimer proteopathic tau seeds are biochemically a forme fruste of mature paired helical filaments","volume":"147","author":"Kumar","year":"2024","journal-title":"Brain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00401-023-02600-1","article-title":"Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau","volume":"146","author":"Welikovitch","year":"2023","journal-title":"Acta Neuropathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.neuron.2021.10.032","article-title":"Rescue of alpha-synuclein aggregation in Parkinson\u2019s patient neurons by synergistic enhancement of ER proteostasis and protein trafficking","volume":"110","author":"Stojkovska","year":"2022","journal-title":"Neuron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1021\/jacsau.3c00579","article-title":"Interplay of alpha-synuclein with Lipid Membranes: Cooperative Adsorption, Membrane Remodeling and Coaggregation","volume":"4","author":"Makasewicz","year":"2024","journal-title":"JACS Au"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6254\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:00:54Z","timestamp":1760032854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,28]]},"references-count":41,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136254"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136254","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3982325\/v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,28]]}}}