{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:58:06Z","timestamp":1790719086572,"version":"4.1.0"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Brain"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Mutations in the LRRK2 gene are a major genetic cause of Parkinson\u2019s disease (PD) and induce hyperphosphorylation of RAB GTPases through increased LRRK2 kinase activity. The phosphatase PPM1H counteracts this activity by selectively dephosphorylating LRRK2-phosphorylated RAB proteins. Here, we used primary\n                    <jats:italic>PPM1H<\/jats:italic>\n                    knockout neurons to investigate how loss of PPM1H and the resulting hyperphosphorylation of RAB proteins affect the distribution of alpha-synuclein (aSyn), a key protein in PD pathology, at presynaptic terminals. We found that PPM1H deficiency significantly increased the distance between aSyn and the presynaptic marker Bassoon, indicating displacement of aSyn away from the presynapse. Pharmacological LRRK2 kinase inhibition rescued this phenotype, restoring intrasynaptic aSyn positioning to wild-type values. These findings show that loss of PPM1H alters aSyn localization in a LRRK2 kinase activity-dependent manner, suggesting that elevated levels of LRRK2-phosphorylated RAB proteins disrupt the nanoscale organization of aSyn at the presynapse.\n                  <\/jats:p>","DOI":"10.1186\/s13041-026-01352-9","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:05:46Z","timestamp":1790651146000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PPM1H loss alters intrasynaptic alpha-synuclein localization in a LRRK2-dependent manner"],"prefix":"10.1186","volume":"19","author":[{"given":"Lennart","family":"Evers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Grein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9701-5273","authenticated-orcid":false,"given":"C. Alexander","family":"Boecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"1","key":"1352_CR1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/ene.14108","volume":"27","author":"R Balestrino","year":"2020","unstructured":"Balestrino R, Schapira AHV. Parkinson disease. Euro J Neurol. 2020;27(1):27\u201342. https:\/\/doi.org\/10.1111\/ene.14108.","journal-title":"Euro J Neurol"},{"issue":"2","key":"1352_CR2","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1080\/15548627.2019.1603545","volume":"16","author":"PW-L Ho","year":"2020","unstructured":"Ho PW-L, Leung CT, Liu H, Pang S-Y-Y, Lam CS-C, Xian J, et al. Age-dependent accumulation of oligomeric SNCA\/\u03b1-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of parkinson disease: role for therapeutic activation of chaperone-mediated autophagy (CMA). Autophagy, Taylor Francis. 2020;16(2):347\u201370. https:\/\/doi.org\/10.1080\/15548627.2019.1603545.","journal-title":"Autophagy, Taylor Francis"},{"issue":"7","key":"1352_CR3","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.4103\/1673-5374.235013","volume":"13","author":"F Miraglia","year":"2018","unstructured":"Miraglia F, Ricci A, Rota L, Colla E. Subcellular localization of alpha-synuclein aggregates and their interaction with membranes. Neural Regen Res. 2018;13(7):1136. https:\/\/doi.org\/10.4103\/1673-5374.235013.","journal-title":"Neural Regen Res"},{"key":"1352_CR4","doi-asserted-by":"publisher","unstructured":"Dhekne HS, Yanatori I, Gomez RC, Tonelli F, Diez F, Sch\u00fcle B, et al. A pathway for Parkinson\u2019s disease LRRK2 kinase to block primary cilia and sonic hedgehog signaling in the brain. Elife. 2018;7:e40202. https:\/\/doi.org\/10.7554\/eLife.40202","DOI":"10.7554\/eLife.40202"},{"key":"1352_CR5","doi-asserted-by":"publisher","unstructured":"Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M, et al. Phosphoproteomics reveals that Parkinson\u2019s disease kinase LRRK2 regulates a subset of rab GTPases. eLife. 2016;5:1\u201328. https:\/\/doi.org\/10.7554\/eLife.12813.","DOI":"10.7554\/eLife.12813"},{"issue":"13","key":"1352_CR6","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1042\/BCJ20253133","volume":"482","author":"B Twellsieck","year":"2025","unstructured":"Twellsieck B, Boecker CA. Role of LRRK2 in axonal transport and Parkinson\u2019s disease. The Biochemical J. 2025;482(13):905\u201319. https:\/\/doi.org\/10.1042\/BCJ20253133.","journal-title":"The Biochemical J"},{"key":"1352_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.50416","volume":"8","author":"K Berndsen","year":"2019","unstructured":"Berndsen K, Lis P, Yeshaw WM, Wawro PS, Nirujogi RS, Wightman M, et al. PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins. eLife. 2019;8:1\u201337. https:\/\/doi.org\/10.7554\/eLife.50416.","journal-title":"eLife"},{"key":"1352_CR8","doi-asserted-by":"publisher","unstructured":"MacIsaac S, Quevedo Melo T, Zhang Y, Volta M, Farrer MJ, Milnerwood AJ. Neuron-autonomous susceptibility to induced synuclein aggregation is exacerbated by endogenous Lrrk2 mutations and ameliorated by Lrrk2 genetic knock-out. Brain Commun. 2020;2(1). https:\/\/doi.org\/10.1093\/braincomms\/fcz052.","DOI":"10.1093\/braincomms\/fcz052"},{"issue":"28","key":"1352_CR9","doi-asserted-by":"publisher","first-page":"7415","DOI":"10.1523\/JNEUROSCI.3642-15.2016","volume":"36","author":"LA Volpicelli-Daley","year":"2016","unstructured":"Volpicelli-Daley LA, Abdelmotilib H, Liu Z, Stoyka L, Daher JPL, Milnerwood AJ, et al. G2019S-LRRK2 expression augments -synuclein sequestration into inclusions in neurons. J Neurosci. 2016;36(28):7415\u201327. https:\/\/doi.org\/10.1523\/JNEUROSCI.3642-15.2016.","journal-title":"J Neurosci"},{"issue":"6","key":"1352_CR10","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1007\/s00401-020-02227-6","volume":"140","author":"Q Wu","year":"2020","unstructured":"Wu Q, Shaikh MA, Meymand ES, Zhang B, Luk KC, Trojanowski JQ, et al. Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo. Acta Neuropathol. 2020;140(6):831\u201349. https:\/\/doi.org\/10.1007\/s00401-020-02227-6.","journal-title":"Acta Neuropathol"},{"key":"1352_CR11","doi-asserted-by":"publisher","unstructured":"Fricke M, Mechel A, Evers L, Twellsieck B, Grein JM, Cima-Omori M-S, et al. Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation. Cell Rep. 2026;45. https:\/\/doi.org\/10.1016\/j.celrep.2026.117364.","DOI":"10.1016\/j.celrep.2026.117364"},{"issue":"1","key":"1352_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40478-021-01283-7","volume":"9","author":"CF Brzozowski","year":"2021","unstructured":"Brzozowski CF, Hijaz BA, Singh V, Gcwensa NZ, Kelly K, Boyden ES, et al. Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of \u03b1-synuclein. Acta Neuropathol Commun. 2021;9(1):1\u201318. https:\/\/doi.org\/10.1186\/s40478-021-01283-7.","journal-title":"Acta Neuropathol Commun"},{"issue":"6","key":"1352_CR13","doi-asserted-by":"publisher","first-page":"117364","DOI":"10.1016\/j.celrep.2026.117364","volume":"45","author":"M Fricke","year":"2026","unstructured":"Fricke M, Mechel A, Evers L, Twellsieck B, Grein JM, Cima-Omori M-S, et al. Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation. Cell Rep. 2026 Apr 17;45(6):117364. https:\/\/doi.org\/10.1016\/j.celrep.2026.117364.","journal-title":"Cell Rep"},{"issue":"10","key":"1352_CR14","doi-asserted-by":"publisher","first-page":"2140","DOI":"10.1016\/j.cub.2021.02.061","volume":"31","author":"CA Boecker","year":"2021","unstructured":"Boecker CA, Goldsmith J, Dou D, Cajka GG, Holzbaur ELF. Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes. Curr Biol, Elsevier Ltd. 2021;31(10):2140\u201354.e6. https:\/\/doi.org\/10.1016\/j.cub.2021.02.061.","journal-title":"Curr Biol, Elsevier Ltd"},{"key":"1352_CR15","doi-asserted-by":"publisher","unstructured":"Dou D, Smith EM, Evans CS, Boecker CA, Holzbaur ELF. Regulatory imbalance between LRRK2 kinase, PPM1H phosphatase, and ARF6 GTPase disrupts the axonal transport of autophagosomes. Cell reports. Elsevier; 2023;42. https:\/\/doi.org\/10.1016\/j.celrep.2023.112448.","DOI":"10.1016\/j.celrep.2023.112448"},{"key":"1352_CR16","doi-asserted-by":"publisher","unstructured":"Dou D, Aiken J, Holzbaur ELF. RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors. J Cell Biol. 2024;223(6):e202307092. https:\/\/doi.org\/10.1083\/jcb.202307092.","DOI":"10.1083\/jcb.202307092"},{"issue":"1","key":"1352_CR17","doi-asserted-by":"publisher","first-page":"9165","DOI":"10.1038\/s41467-026-75194-3","volume":"17","author":"C Chen","year":"2026","unstructured":"Chen C, He Q, Tombesi G, Napier E, Jaconelli M, Moreno-Ramos OA, et al. Leucine-rich repeat kinase 2 impairs the release sites of Parkinson\u2019s disease vulnerable dopamine axons. Nat Commun, Nat Publishing Group. 2026;17(1):9165. https:\/\/doi.org\/10.1038\/s41467-026-75194-3.","journal-title":"Nat Commun, Nat Publishing Group"},{"issue":"2","key":"1352_CR18","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1111\/jnc.15240","volume":"157","author":"F Pischedda","year":"2021","unstructured":"Pischedda F, Piccoli G. LRRK2 at the pre-synaptic site: a 16-years perspective. J Neurochem. 2021;157(2):297\u2013311. https:\/\/doi.org\/10.1111\/jnc.15240.","journal-title":"J Neurochem"}],"container-title":["Molecular Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13041-026-01352-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-026-01352-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-026-01352-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:01:34Z","timestamp":1790715694000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13041-026-01352-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":18,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1352"],"URL":"https:\/\/doi.org\/10.1186\/s13041-026-01352-9","relation":{},"ISSN":["1756-6606"],"issn-type":[{"value":"1756-6606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"assertion":[{"value":"21 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 September 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All experiments were approved by the local animal research council and complied with the legislation for the management and care of laboratory animals in the state of Lower Saxony, Germany.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"66"}}