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It has been shown that Lrrk2 knockout (KO) rodents have enlarged lamellar bodies (LBs) in their alveolar epithelial type II cells, although the underlying mechanisms remain unclear. Here we performed proteomic analyses on LBs isolated from Lrrk2 KO mice and found that the LB proteome is substantially different in Lrrk2 KO mice compared with wild-type mice. In Lrrk2 KO LBs, several Rab proteins were increased, and subunit proteins of BLOC-1-related complex (BORC) were decreased. The amount of surfactant protein C was significantly decreased in the bronchoalveolar lavage fluid obtained from Lrrk2 KO mice, suggesting that LB exocytosis is impaired in Lrrk2 KO mice. We also found that the enlargement of LBs is recapitulated in A549 cells upon KO of LRRK2 or by treating cells with LRRK2 inhibitors. Using this model, we show that KO of BORCS6, a BORC subunit gene, but not other BORC genes, causes LB enlargement. Our findings implicate the LRRK2-BORCS6 pathway in the maintenance of LB morphology.<\/jats:p>","DOI":"10.1093\/hmg\/ddab146","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T15:14:12Z","timestamp":1622042052000},"page":"1618-1631","source":"Crossref","is-referenced-by-count":12,"title":["BORCS6 is involved in the enlargement of lung lamellar bodies in\n                    <i>Lrrk2<\/i>\n                    knockout mice"],"prefix":"10.1093","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9516-6868","authenticated-orcid":false,"given":"Miho","family":"Araki","sequence":"first","affiliation":[{"name":"Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9119-4714","authenticated-orcid":false,"given":"Kyohei","family":"Ito","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3925-4011","authenticated-orcid":false,"given":"Sho","family":"Takatori","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6370-1099","authenticated-orcid":false,"given":"Genta","family":"Ito","sequence":"additional","affiliation":[{"name":"Social Cooperation Program of Brain and Neurological Disorders, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0075-5943","authenticated-orcid":false,"given":"Taisuke","family":"Tomita","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan"},{"name":"Social Cooperation Program of Brain and Neurological Disorders, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"key":"2021081712011810000_ref1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.neuron.2004.10.023","article-title":"Cloning of the gene containing mutations that cause PARK8-linked Parkinson\u2019s disease","volume":"44","author":"Pais\u00e1n-Ru\u00edz","year":"2004","journal-title":"Neuron"},{"key":"2021081712011810000_ref2","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.neuron.2004.11.005","article-title":"Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology","volume":"44","author":"Zimprich","year":"2004","journal-title":"Neuron"},{"key":"2021081712011810000_ref3","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1111\/jnc.13691","article-title":"The clinical symptoms of Parkinson\u2019s disease","volume":"139","author":"Sveinbjornsdottir","year":"2016","journal-title":"J. Neurochem."},{"key":"2021081712011810000_ref4","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1038\/ng.485","article-title":"Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson\u2019s disease","volume":"41","author":"Satake","year":"2009","journal-title":"Nat. Genet."},{"key":"2021081712011810000_ref5","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1038\/ng.487","article-title":"Genome-wide association study reveals genetic risk underlying Parkinson\u2019s disease","volume":"41","author":"Sim\u00f3n-S\u00e1nchez","year":"2009","journal-title":"Nat. Genet."},{"key":"2021081712011810000_ref6","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0043472","article-title":"Biochemical characterization of highly purified leucine-rich repeat kinases 1 and 2 demonstrates formation of homodimers","volume":"7","author":"Civiero","year":"2012","journal-title":"PLoS One"},{"key":"2021081712011810000_ref7","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1042\/BST20120088","article-title":"Analysis of LRRK2 accessory repeat domains: prediction of repeat length, number and sites of Parkinson\u2019s disease mutations","volume":"40","author":"Mills","year":"2012","journal-title":"Biochem. Soc. Trans."},{"key":"2021081712011810000_ref8","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.bbapap.2011.12.009","article-title":"Expression, purification and preliminary biochemical and structural characterization of the leucine rich repeat namesake domain of leucine rich repeat kinase 2","volume":"1824","author":"Vancraenenbroeck","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"2021081712011810000_ref9","doi-asserted-by":"crossref","DOI":"10.1042\/NS20180005","article-title":"Physiological and pathological functions of LRRK2: implications from substrate proteins","volume":"2","author":"Araki","year":"2018","journal-title":"Neuronal Signal."},{"key":"2021081712011810000_ref10","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.12813","article-title":"Phosphoproteomics reveals that Parkinson\u2019s disease kinase LRRK2 regulates a subset of Rab GTPases","volume":"5","author":"Steger","year":"2016","journal-title":"elife"},{"key":"2021081712011810000_ref11","doi-asserted-by":"crossref","first-page":"2671","DOI":"10.1042\/BCJ20160557","article-title":"Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors","volume":"473","author":"Ito","year":"2016","journal-title":"Biochem. 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A."},{"key":"2021081712011810000_ref14","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.31012","article-title":"Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis","volume":"6","author":"Steger","year":"2017","journal-title":"elife"},{"key":"2021081712011810000_ref15","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/ana.20791","article-title":"Biochemical and pathological characterization of Lrrk2","volume":"59","author":"Giasson","year":"2006","journal-title":"Ann. Neurol."},{"key":"2021081712011810000_ref16","doi-asserted-by":"crossref","first-page":"4209","DOI":"10.1093\/hmg\/ddr348","article-title":"LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice","volume":"20","author":"Herzig","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"2021081712011810000_ref17","doi-asserted-by":"crossref","first-page":"273ra15","DOI":"10.1126\/scitranslmed.aaa3634","article-title":"Effect of selective LRRK2 kinase inhibition on nonhuman primate lung","volume":"7","author":"Fuji","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"2021081712011810000_ref18","doi-asserted-by":"crossref","DOI":"10.1016\/j.tiv.2020.105012","article-title":"An in vitro alveolar epithelial cell model recapitulates LRRK2 inhibitor-induced increases in lamellar body size observed in preclinical models","volume":"70","author":"Harney","year":"2021","journal-title":"Toxicol. in Vitro"},{"key":"2021081712011810000_ref19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.tox.2018.01.003","article-title":"PFE-360-induced LRRK2 inhibition induces reversible, non-adverse renal changes in rats","volume":"395","author":"Andersen","year":"2018","journal-title":"Toxicology"},{"key":"2021081712011810000_ref20","doi-asserted-by":"crossref","first-page":"L243","DOI":"10.1152\/ajplung.00242.2009","article-title":"Altered lung surfactant system in a Rab38-deficient rat model of Hermansky-Pudlak syndrome","volume":"298","author":"Osanai","year":"2010","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2021081712011810000_ref21","doi-asserted-by":"crossref","first-page":"4078","DOI":"10.1093\/hmg\/ddv147","article-title":"Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury","volume":"24","author":"Boddu","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2021081712011810000_ref22","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1093\/hmg\/ddy232","article-title":"Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice","volume":"27","author":"Pellegrini","year":"2018","journal-title":"Hum. Mol. 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Cell Biol."},{"key":"2021081712011810000_ref28","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.devcel.2015.02.011","article-title":"BORC, a multisubunit complex that regulates lysosome positioning","volume":"33","author":"Pu","year":"2015","journal-title":"Dev. Cell"},{"key":"2021081712011810000_ref29","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0016482","article-title":"Comparative proteomic analysis of lung lamellar bodies and lysosome-related organelles","volume":"6","author":"Ridsdale","year":"2011","journal-title":"PLoS One"},{"key":"2021081712011810000_ref30","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/0005-2760(80)90222-2","article-title":"Phospholipid composition and ultrastructure of A549 cells and other cultured pulmonary epithelial cells of presumed type II cell origin","volume":"617","author":"Mason","year":"1980","journal-title":"Biochim. Biophys. 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Adv."},{"key":"2021081712011810000_ref34","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1165\/rcmb.2003-0264OC","article-title":"Rab3D and actin reveal distinct lamellar body subpopulations in alveolar epithelial type II cells","volume":"30","author":"Weeren","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2021081712011810000_ref35","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1016\/j.celrep.2016.10.062","article-title":"BORC functions upstream of kinesins 1 and 3 to coordinate regional movement of lysosomes along different microtubule tracks","volume":"17","author":"Guardia","year":"2016","journal-title":"Cell Rep."},{"key":"2021081712011810000_ref36","doi-asserted-by":"crossref","first-page":"4199","DOI":"10.1083\/jcb.201703061","article-title":"LAMTOR\/Ragulator is a negative regulator of Arl8b- and BORC-dependent late endosomal positioning","volume":"216","author":"Filipek","year":"2017","journal-title":"J. Cell Biol."},{"key":"2021081712011810000_ref37","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1016\/j.celrep.2015.07.052","article-title":"Disruption of the rag-Ragulator complex by c17orf59 inhibits mTORC1","volume":"12","author":"Schweitzer","year":"2015","journal-title":"Cell Rep."},{"key":"2021081712011810000_ref38","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1074\/mcp.T500024-MCP200","article-title":"Phosphate-binding tag, a new tool to visualize phosphorylated proteins","volume":"5","author":"Kinoshita","year":"2006","journal-title":"Mol. Cell. Proteomics"},{"key":"2021081712011810000_ref39","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aav0820","article-title":"LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits","volume":"12","author":"Baptista","year":"2020","journal-title":"Sci. Transl. 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