{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:29:20Z","timestamp":1768512560898,"version":"3.49.0"},"posted":{"date-parts":[[2024,6,24]]},"group-title":"Neuroscience","reference-count":54,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Alpha-synuclein (\u03b1syn) is the key pathogenic protein implicated in synucleinopathies including Parkinson\u2019s Disease (PD) and Dementia with Lewy Bodies (DLB). In these diseases, \u03b1syn is thought to spread between cells where it accumulates and induces pathology; however, mechanisms that drive its propagation or aggregation are poorly understood. We have previously reported that the small GTPase Rab27b is elevated in human PD and DLB and that it can mediate the autophagic clearance and toxicity of \u03b1syn in a paracrine \u03b1syn cell culture neuronal model. Here, we expanded our previous work and further characterized a role for Rab27b in neuronal lysosomal processing and \u03b1syn clearance. We found that Rab27b KD in this \u03b1syn inducible neuronal model resulted in lysosomal dysfunction and increased \u03b1syn levels in lysosomes. Similar lysosomal proteolytic defects and enzymatic dysfunction were observed in both primary neuronal cultures and brain lysates from Rab27b knockout (KO) mice. \u03b1Syn aggregation was exacerbated in Rab27b KO neurons upon treatment with \u03b1syn preformed fibrils. We found no changes in lysosomal counts or lysosomal pH in either model, but we did identify defects in acidic vesicle trafficking in Rab27b KO primary neurons which may drive lysosomal dysfunction and promote \u03b1syn aggregation. Rab27b OE enhanced lysosomal activity and reduced insoluble \u03b1syn accumulation. Finally we found elevated Rab27b levels in human postmortem incidental Lewy Body Disease (iLBD) subjects relative to healthy controls. These data suggest a role for Rab27b in neuronal lysosomal activity and identify it as a potential therapeutic target in synucleinopathies.<\/jats:p>","DOI":"10.1101\/2024.06.20.599785","type":"posted-content","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T04:40:12Z","timestamp":1719204012000},"source":"Crossref","is-referenced-by-count":1,"title":["Rab27b promotes lysosomal function and alpha-synuclein clearance in neurons"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8724-5454","authenticated-orcid":false,"given":"Kasandra","family":"Scholz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3597-7423","authenticated-orcid":false,"given":"Rudradip","family":"Pattanayak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekkatine","family":"Roschonporn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0019-0740","authenticated-orcid":false,"given":"Frank Sanders","family":"Pair","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amber","family":"Nobles","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2227-7310","authenticated-orcid":false,"given":"Talene A.","family":"Yacoubian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024062509150628000_2024.06.20.599785v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30295-3"},{"key":"2024062509150628000_2024.06.20.599785v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2011.11.015"},{"key":"2024062509150628000_2024.06.20.599785v1.3","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000247740.47667.03"},{"key":"2024062509150628000_2024.06.20.599785v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/42166"},{"key":"2024062509150628000_2024.06.20.599785v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3955"},{"key":"2024062509150628000_2024.06.20.599785v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2009.06324.x"},{"key":"2024062509150628000_2024.06.20.599785v1.7","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-02057-1"},{"key":"2024062509150628000_2024.06.20.599785v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2013.03.005"},{"key":"2024062509150628000_2024.06.20.599785v1.9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801992200"},{"key":"2024062509150628000_2024.06.20.599785v1.10","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009357"},{"key":"2024062509150628000_2024.06.20.599785v1.11","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-017-0154-3"},{"key":"2024062509150628000_2024.06.20.599785v1.12","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-15-4272-52"},{"key":"2024062509150628000_2024.06.20.599785v1.13","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-014-8787-5"},{"issue":"8","key":"2024062509150628000_2024.06.20.599785v1.14","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1016\/j.jmb.2020.01.037","article-title":"Autophagy in Parkinson\u2019s Disease","volume":"432","year":"2020","journal-title":"J Mol Biol"},{"key":"2024062509150628000_2024.06.20.599785v1.15","doi-asserted-by":"crossref","unstructured":"Fellner, L. , et al., Autophagy in \u03b1-Synucleinopathies-An Overstrained System. Cells, 2021. 10(11).","DOI":"10.3390\/cells10113143"},{"issue":"2","key":"2024062509150628000_2024.06.20.599785v1.16","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41419-019-1364-0","article-title":"A30P mutant \u03b1-synuclein impairs autophagic flux by inactivating JNK signaling to enhance ZKSCAN3 activity in midbrain dopaminergic neurons","volume":"10","year":"2019","journal-title":"Cell Death Dis"},{"key":"2024062509150628000_2024.06.20.599785v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26477"},{"key":"2024062509150628000_2024.06.20.599785v1.18","doi-asserted-by":"crossref","unstructured":"Navarro-Romero, A. , M. Montpey\u00f3 , and M. Martinez-Vicente , The Emerging Role of the Lysosome in Parkinson\u2019s Disease. Cells, 2020. 9(11).","DOI":"10.3390\/cells9112399"},{"key":"2024062509150628000_2024.06.20.599785v1.19","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25462"},{"key":"2024062509150628000_2024.06.20.599785v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2019.10.002"},{"key":"2024062509150628000_2024.06.20.599785v1.21","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0336-2"},{"key":"2024062509150628000_2024.06.20.599785v1.22","doi-asserted-by":"publisher","DOI":"10.4161\/auto.21011"},{"key":"2024062509150628000_2024.06.20.599785v1.23","doi-asserted-by":"publisher","DOI":"10.1111\/FEBS.15453"},{"key":"2024062509150628000_2024.06.20.599785v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2728"},{"key":"2024062509150628000_2024.06.20.599785v1.25","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2001.5072"},{"key":"2024062509150628000_2024.06.20.599785v1.26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005995"},{"key":"2024062509150628000_2024.06.20.599785v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.02.010"},{"issue":"7","key":"2024062509150628000_2024.06.20.599785v1.28","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1042\/EBC20210016","article-title":"Rab GTPases in Parkinson\u2019s disease: a primer","volume":"65","year":"2021","journal-title":"Essays Biochem"},{"key":"2024062509150628000_2024.06.20.599785v1.29","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ceb.2019.03.009","article-title":"The role of Rab GTPases in the pathobiology of Parkinson\u2019 disease","volume":"59","year":"2019","journal-title":"Curr Opin Cell Biol"},{"key":"2024062509150628000_2024.06.20.599785v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2000"},{"key":"2024062509150628000_2024.06.20.599785v1.31","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E05-12-1170"},{"key":"2024062509150628000_2024.06.20.599785v1.32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.013337"},{"key":"2024062509150628000_2024.06.20.599785v1.33","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1134-18.2018"},{"key":"2024062509150628000_2024.06.20.599785v1.34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0609879104"},{"issue":"1","key":"2024062509150628000_2024.06.20.599785v1.35","doi-asserted-by":"crossref","first-page":"9837","DOI":"10.1038\/s41598-022-13557-8","article-title":"Deletion in chromosome 6 spanning alpha-synuclein and multimerin1 loci in the Rab27a\/b double knockout mouse","volume":"12","year":"2022","journal-title":"Sci Rep"},{"key":"2024062509150628000_2024.06.20.599785v1.36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.132197599"},{"key":"2024062509150628000_2024.06.20.599785v1.37","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1134-18.2018"},{"key":"2024062509150628000_2024.06.20.599785v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2009.03.005"},{"key":"2024062509150628000_2024.06.20.599785v1.39","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.65.8.1074"},{"key":"2024062509150628000_2024.06.20.599785v1.40","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0345-7"},{"key":"2024062509150628000_2024.06.20.599785v1.41","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25952"},{"key":"2024062509150628000_2024.06.20.599785v1.42","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002102"},{"issue":"1","key":"2024062509150628000_2024.06.20.599785v1.43","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s40478-020-01026-0","article-title":"Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy","volume":"8","year":"2020","journal-title":"Acta Neuropathol Commun"},{"issue":"2","key":"2024062509150628000_2024.06.20.599785v1.44","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/neup.12348","article-title":"An order in Lewy body disorders: Retrograde degeneration in hyperbranching axons as a fundamental structural template accounting for focal\/multifocal Lewy body disease","volume":"37","year":"2017","journal-title":"Neuropath"},{"key":"2024062509150628000_2024.06.20.599785v1.45","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27823"},{"key":"2024062509150628000_2024.06.20.599785v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.08.033"},{"key":"2024062509150628000_2024.06.20.599785v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.06.013"},{"key":"2024062509150628000_2024.06.20.599785v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2018.02.020"},{"key":"2024062509150628000_2024.06.20.599785v1.49","doi-asserted-by":"crossref","unstructured":"Roney, J.C. , X.T. Cheng , and Z.H. Sheng , Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis. J Cell Biol, 2022. 221(3).","DOI":"10.1083\/jcb.202111077"},{"key":"2024062509150628000_2024.06.20.599785v1.50","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1292-22.2022"},{"key":"2024062509150628000_2024.06.20.599785v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.02.032"},{"issue":"18","key":"2024062509150628000_2024.06.20.599785v1.52","first-page":"e3362","article-title":"Subcellular Fractionation of Hela Cells for Lysosome Enrichment Using a Continuous Percoll-Density Gradient","volume":"9","year":"2019","journal-title":"Bio Protoc"},{"issue":"1","key":"2024062509150628000_2024.06.20.599785v1.53","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s40478-019-0872-6","article-title":"Impaired \u03b2-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations","volume":"7","year":"2019","journal-title":"Acta Neuropathol Commun"},{"key":"2024062509150628000_2024.06.20.599785v1.54","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12456"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.06.20.599785","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:36:18Z","timestamp":1768458978000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.06.20.599785"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,24]]},"references-count":54,"URL":"https:\/\/doi.org\/10.1101\/2024.06.20.599785","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1523\/JNEUROSCI.1579-24.2025","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,6,24]]},"subtype":"preprint"}}