{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:29:42Z","timestamp":1787016582570,"version":"build-2736575974"},"reference-count":35,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"893","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:p>\n                    Parkinson\u2019s disease is associated with activating mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), which suppresses primary cilia formation in cholinergic and parvalbumin interneurons and astrocytes in the striatum. As a result, there is a decrease in the production of neuroprotective glial cell line\u2013derived neurotrophic factor (GDNF) and neurturin (NRTN), which normally support the viability of dopaminergic neurons. MLi-2 is a brain-penetrant, selective, and now experimental inhibitor of LRRK2. Here, we found that dietary administration of MLi-2 to young LRRK2-mutant mice for 3 months restored primary cilia formation and Hedgehog signaling in both cholinergic and parvalbumin interneurons and astrocytes. The treatment also restored the Hedgehog-responsive expression of\n                    <jats:italic>Gdnf<\/jats:italic>\n                    and\n                    <jats:italic>Nrtn<\/jats:italic>\n                    in the neurons. Cilia were also restored on cholinergic neurons of the pedunculopontine nucleus, where their loss correlates with severity of motor impairment in patients. Furthermore, MLi-2 increased the density of fine striatal dopaminergic processes and decreased the amount of stress-associated Sonic Hedgehog RNA expression in nigral dopaminergic neurons. Thus, pathogenic LRRK2-driven cilia loss is reversible in postmitotic neurons and astrocytes, which suggests that early administration of specific LRRK2 inhibitors may therapeutically benefit patients.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.ads5761","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T13:58:08Z","timestamp":1751378288000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":14,"title":["Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson\u2019s disease\u2013linked\n                    <i>LRRK2<\/i>\n                    -mutant mice"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6845-2095","authenticated-orcid":true,"given":"Ebsy","family":"Jaimon","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, 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UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7325-3303","authenticated-orcid":true,"given":"Odetta","family":"Antico","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA."},{"name":"MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2140-9185","authenticated-orcid":true,"given":"Dario R.","family":"Alessi","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA."},{"name":"MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6462-984X","authenticated-orcid":true,"given":"Suzanne 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