{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T07:27:42Z","timestamp":1786433262489,"version":"build-2736575974"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"31","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018231","name":"Aligning Science Across Parkinson's","doi-asserted-by":"publisher","award":["ASAP-000463"],"award-info":[{"award-number":["ASAP-000463"]}],"id":[{"id":"10.13039\/100018231","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ara Parseghian Medical Research Foundation","award":["Not applicable"],"award-info":[{"award-number":["Not applicable"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,8,5]]},"abstract":"<jats:p>\n                    Parkinson\u2019s disease is characterized by loss of dopamine neurons that project to the dorsal striatum, and mutations in\n                    <jats:italic toggle=\"yes\">LRRK2<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">GBA1<\/jats:italic>\n                    are the most common genetic causes of familial Parkinson\u2019s disease. Previously, we showed that pathogenic\n                    <jats:italic toggle=\"yes\">LRRK2<\/jats:italic>\n                    mutations inhibit primary cilia formation in rare interneurons and astrocytes of the mouse and human dorsal striatum. This blocks Hedgehog signaling and reduces synthesis of neuroprotective GDNF and NRTN, which normally support dopamine neurons vulnerable in PD. Here, we show that\n                    <jats:italic toggle=\"yes\">GBA1<\/jats:italic>\n                    mutations also impair Hedgehog signaling and Hedgehog-dependent neuroprotective factor production by a distinct mechanism. Loss of GBA1 activity increases lysosomal accessible cholesterol and thus decreases accessible cholesterol in primary cilia of cultured cells; this change in lipid composition blocks ciliary Hedgehog signaling that depends on accessible cholesterol. Consistent with defects in Hedgehog signaling in the mouse dorsal striatum,\n                    <jats:italic toggle=\"yes\">GBA1<\/jats:italic>\n                    mutant mice show reduced Hedgehog-induced\n                    <jats:italic toggle=\"yes\">Gdnf<\/jats:italic>\n                    RNA expression in striatal cholinergic interneurons, with no detectable impact on cilia formation. Also, both\n                    <jats:italic toggle=\"yes\">LRRK2<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">GBA1<\/jats:italic>\n                    mutations suppress Hedgehog-induced\n                    <jats:italic toggle=\"yes\">Bdnf<\/jats:italic>\n                    expression in striatal astrocytes. These findings underscore the role of Hedgehog signaling in the nigrostriatal circuit and reveal a convergent mechanism by which distinct\n                    <jats:italic toggle=\"yes\">LRRK2<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">GBA1<\/jats:italic>\n                    mutations may contribute to PD pathogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2504774122","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T17:39:07Z","timestamp":1753897147000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["Lysosomal glucocerebrosidase is needed for ciliary Hedgehog signaling: A convergent pathway contributing to Parkinson\u2019s disease"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2765-1244","authenticated-orcid":false,"given":"Sreeja V.","family":"Nair","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Stanford University School of Medicine","place":["Stanford"]},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network","place":["Chevy Chase"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6845-2095","authenticated-orcid":false,"given":"Ebsy","family":"Jaimon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Stanford University School of Medicine","place":["Stanford"]},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network","place":["Chevy Chase"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8525-3263","authenticated-orcid":false,"given":"Ayan","family":"Adhikari","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Stanford University School of Medicine","place":["Stanford"]},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network","place":["Chevy Chase"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Nikoloff","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Stanford University School of Medicine","place":["Stanford"]},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network","place":["Chevy Chase"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6462-984X","authenticated-orcid":false,"given":"Suzanne R.","family":"Pfeffer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Stanford University School of Medicine","place":["Stanford"]},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network","place":["Chevy Chase"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.01.018"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2015.03.013"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001315"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11081261"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.104782"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2018.12.014"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28066"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-022-00281-6"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.05.018"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2402206121"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202402922"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.40202"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.67900"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","unstructured":"E. Jaimon Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson\u2019s linked-LRRK2 mutant mice. Sci Signal. 893 eads5761 (2025).","DOI":"10.1126\/scisignal.ads5761"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.25466"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-020-00678-2"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3513311"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.TM118.004165"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118951"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a002932"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21072566"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2213886120"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202105060"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2015.02.008"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mie.2021.01.011"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.70504"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abm5563"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27119"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0252325"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.20304"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","unstructured":"E. Bagnoli Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain. Proc. Natl. Acad. Sci. U.S.A. 122 e2412029122 (2025).","DOI":"10.1073\/pnas.2412029122"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.06.001"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.29074"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuro.2009.06.009"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2018.03.008"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1525-17.2017"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2014.128"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12639"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12606"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01401-9"},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","unstructured":"Z. Gaertner Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2(G2019S) model of Parkinson\u2019s disease. eLife 13 RP101035 (2025).","DOI":"10.7554\/eLife.101035.3"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.07.026"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.09.032"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1607"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/75556"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyad031"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-021-04344-9"},{"key":"e_1_3_4_52_2","doi-asserted-by":"crossref","unstructured":"S. V. Nair Lysosomal Glucocerebrosidase is needed for ciliary Hedgehog signaling: A convergent pathway to Parkinson\u2019s disease. Zenodo. https:\/\/doi.org\/10.5281\/zenodo.12753029. Deposited 30 June 2025","DOI":"10.1101\/2025.01.20.633968"},{"key":"e_1_3_4_53_2","doi-asserted-by":"crossref","unstructured":"S. V. Nair Lysosomal Glucocerebrosidase is needed for ciliary Hedgehog signaling: A convergent pathway to Parkinson\u2019s disease. Zenodo. https:\/\/doi.org\/10.5281\/zenodo.15801264. Deposited 11 July 2025.","DOI":"10.1101\/2025.01.20.633968"},{"key":"e_1_3_4_54_2","doi-asserted-by":"crossref","unstructured":"S. V. Nair E. Jaimon A. Adhikari J. Nikoloff S. R. Pfeffer Lysosomal Glucocerebrosidase is needed for ciliary Hedgehog signaling: A convergent pathway to Parkinson\u2019s disease. bioRxiv [Preprint] (2025). https:\/\/doi.org\/10.1101\/2025.01.20.633968 (Accessed 21 January 2025).","DOI":"10.1101\/2025.01.20.633968"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2504774122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T17:39:11Z","timestamp":1753897151000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2504774122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":54,"journal-issue":{"issue":"31","published-print":{"date-parts":[[2025,8,5]]}},"alternative-id":["10.1073\/pnas.2504774122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2504774122","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.01.20.633968","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,30]]},"assertion":[{"value":"2025-02-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2504774122"}}