{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:40:23Z","timestamp":1791499223726,"version":"4.3.4"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["GR-2016-02362548"],"award-info":[{"award-number":["GR-2016-02362548"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Chronic neuroinflammation plays a crucial role in the progression of neurodegenerative diseases (NDs), including Parkinson\u2019s disease (PD) and Alzheimer\u2019s disease (AD). Leucine-Rich Repeat Kinase 2 (LRRK2), a gene linked to familial and sporadic PD, has been positively associated with neuroinflammation in both in vitro and in vivo systems. These observations suggest that LRRK2 might actively contribute to neuronal damage and degeneration in NDs. Based on these premises, we explored the impact of LRRK2-mediated neuroinflammation on neurons in a PD- and AD-related context. We set up a cellular model composed of human induced pluripotent stem cell (hiPSC)-derived neurons (dopaminergic for PD and cholinergic for AD) exposed to inflamed glial medium [\u03b1-synuclein pre-formed fibrils (\u03b1-syn pffs) for PD and amyloid-\u03b2 (A\u03b2)1\u201342 fibrils for AD] for several days. To dissect the effect of neuroinflammation, and specifically, the role of LRRK2, on neuronal functions, we first performed transcriptome analysis, and then, we validated the results at functional levels. Interestingly, we found that LRRK2-dependent neuroinflammation contributes to neuronal dysfunctions and death in both ND contexts and that LRRK2 kinase inhibition prevents these detrimental effects. Overall, our results suggest that lowering neuroinflammation through LRRK2 pharmacological inhibition might limit the progression of NDs and thus be neuroprotective.<\/jats:p>","DOI":"10.3390\/biom15091322","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T07:33:02Z","timestamp":1758007982000},"page":"1322","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["LRRK2-Mediated Neuroinflammation Induces Neuronal Dysfunctions in a Parkinson\u2019s and Alzheimer\u2019s Disease Cellular Model"],"prefix":"10.3390","volume":"15","author":[{"given":"Veronica","family":"Mutti","sequence":"first","affiliation":[{"name":"Unit of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8096-9417","authenticated-orcid":false,"given":"Giulia","family":"Carini","sequence":"additional","affiliation":[{"name":"Unit of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3749-2988","authenticated-orcid":false,"given":"Moira","family":"Marizzoni","sequence":"additional","affiliation":[{"name":"Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Filippini","sequence":"additional","affiliation":[{"name":"Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9716-5327","authenticated-orcid":false,"given":"Federica","family":"Bono","sequence":"additional","affiliation":[{"name":"Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0676-9833","authenticated-orcid":false,"given":"Chiara","family":"Fiorentini","sequence":"additional","affiliation":[{"name":"Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2900-7794","authenticated-orcid":false,"given":"Samantha","family":"Saleri","sequence":"additional","affiliation":[{"name":"Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6869-5337","authenticated-orcid":false,"given":"Floriana","family":"De Cillis","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"},{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Gennarelli","sequence":"additional","affiliation":[{"name":"Unit of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy"},{"name":"Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0146-1031","authenticated-orcid":false,"given":"Paolo","family":"Martini","sequence":"additional","affiliation":[{"name":"Unit of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Russo","sequence":"additional","affiliation":[{"name":"Unit of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy"},{"name":"Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Adamu, A., Li, S., Gao, F., and Xue, G. 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