{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T22:02:41Z","timestamp":1773007361783,"version":"3.50.1"},"reference-count":60,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20221225"],"award-info":[{"award-number":["BK20221225"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014717","name":"Youth Science Fund Project","doi-asserted-by":"publisher","award":["81901299"],"award-info":[{"award-number":["81901299"]}],"id":[{"id":"10.13039\/100014717","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Neuroinflammation driven by dysregulated microglial activation exacerbates dopaminergic neuron loss in Parkinson's disease (PD). This study investigated whether the transcription factor SIX2 mitigates neuroinflammation and provides neuroprotection by promoting microglial M2 polarization and exosome\u2010mediated communication.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using LPS\u2010stimulated BV2 microglia and MPTP\u2010induced mouse models of PD, we systematically investigated the role of SIX2. Gain\u2010 and loss\u2010of\u2010function approaches for SIX2, DDIT4, miR\u20103470b, and GREM1 were combined with ChIP, RNA\u2010seq, exosome isolation\/transfer, and behavioral tests to analyze the SIX2\u2010DDIT4\u2010autophagy axis and the exosomal miR\u20103470b\/GREM1\/TGF\u2010\u03b2 pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>RNA\u2010seq and ChIP\u2010qPCR revealed that SIX2 transcriptionally activated DDIT4. This led to mTOR inhibition and autophagy induction, driving a shift in microglial phenotype from pro\u2010inflammatory M1 to protective M2. Consequently, M2\u2010polarized microglia released exosomes highly enriched in miR\u20103470b, as identified by miRNA sequencing. Upon internalization by dopaminergic neurons, miR\u20103470b directly bound to and suppressed GREM1, which in turn potentiated TGF\u2010\u03b2 signaling activity. Ultimately, this SIX2\u2010initiated cascade rescued neuronal apoptosis and restored motor coordination in both cellular and animal models of PD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>SIX2 promotes microglial M2 polarization via the DDIT4\/mTOR\/autophagy axis and mediates neuroprotection through exosomal miR\u20103470b targeting of GREM1\/TGF\u2010\u03b2 signaling, revealing novel therapeutic targets for PD immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70756","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T10:38:01Z","timestamp":1771324681000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>SIX2<\/scp>\n                    \u2010Mediated Microglial\n                    <scp>M2<\/scp>\n                    Polarization and Exosomal\n                    <scp>miR<\/scp>\n                    \u20103470b Delivery Protect Dopaminergic Neurons in Parkinson's Disease"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1834-1715","authenticated-orcid":false,"given":"Jia\u2010shuo","family":"Kan","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Cellular Biology Xuzhou Medical University  Xuzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia\u2010yin","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Cellular Biology Xuzhou Medical University  Xuzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010xin","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Cellular Biology Xuzhou Medical University  Xuzhou Jiangsu 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