{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T11:38:30Z","timestamp":1793014710202,"version":"4.5.0"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T00:00:00Z","timestamp":1730764800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001866","name":"Fonds National de la Recherche Luxembourg","doi-asserted-by":"publisher","award":["C21\/BM\/15850547\/PINK1\u2010DiaPDs"],"award-info":[{"award-number":["C21\/BM\/15850547\/PINK1\u2010DiaPDs"]}],"id":[{"id":"10.13039\/501100001866","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001866","name":"Fonds National de la Recherche Luxembourg","doi-asserted-by":"publisher","award":["FNR\/NCER13\/BM\/11264123"],"award-info":[{"award-number":["FNR\/NCER13\/BM\/11264123"]}],"id":[{"id":"10.13039\/501100001866","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Parkinson's disease (PD) is the second most common, and the fastest\u2010growing neurodegenerative disorder with unclear etiology in most cases. Therefore, the identification of non\u2010genetic risk factors for PD pathology is crucial to develop effective preventative or therapeutic strategies. An increasing number of evidence suggests that central insulin resistance might have an essential role in PD pathology. Nevertheless, it is not clear whether insulin resistance arises from external factors\/lifestyle, comorbidities such as type 2 diabetes or it can occur in a PD patient's brain independently from peripheral insulin resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      We aimed to investigate insulin resistance and its role in\n                      <jats:italic>GBA1<\/jats:italic>\n                      \u00a0mutation\u2010associated PD pathogenesis and phenotype severity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Midbrain organoids, generated from induced pluripotent stem cells (iPSCs) of PD patients carrying the\n                      <jats:italic>GBA1<\/jats:italic>\n                      \u2010N370S heterozygous mutation (GBA\u2010PD) and healthy donors, were exposed to different insulin concentrations to modify insulin signaling function. Transcriptomics analysis was performed to explore insulin signaling gene expression patterns in GBA\u2010PD and to find a potential target for GBA\u2010PD\u2010associated phenotype rescue.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The insulin signaling pathway genes show dysregulation in GBA\u2010PD. Particularly, we highlight that a knockdown of\n                      <jats:italic>FOXO1<\/jats:italic>\n                      mitigates the loss of dopaminergic neurons and cellular death in GBA\u2010PD. Additionally, our findings suggest a promising therapeutic potential of the anti\u2010diabetic drug Pioglitazone in decreasing dopaminergic neuron loss associated with GBA\u2010PD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Local insulin signaling dysfunction plays a substantial role in GBA\u2010PD pathogenesis, exacerbating dopaminergic neuron death. \u00a9 2024 The Author(s).\n                      <jats:italic>Movement Disorders<\/jats:italic>\n                      published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  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