{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:42:59Z","timestamp":1789764179603,"version":"4.0.1"},"reference-count":49,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T00:00:00Z","timestamp":1637798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM133440"],"award-info":[{"award-number":["R35GM133440"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001906","name":"Washington Research Foundation","doi-asserted-by":"publisher","award":["135286"],"award-info":[{"award-number":["135286"]}],"id":[{"id":"10.13039\/100001906","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s Disease (PD) is the most common movement disorder, and the strongest genetic risk factor for PD is mutations in the glucocerebrosidase gene (GBA). Mutations in GBA also lead to the development of Gaucher Disease (GD), the most common type of lysosomal storage disorder. Current therapeutic approaches fail to address neurological GD symptoms. Therefore, identifying therapeutic strategies that improve the phenotypic traits associated with GD\/PD in animal models may provide an opportunity for treating neurological manifestations of GD\/PD. Thiazolidinediones (TZDs, also called glitazones) are a class of compounds targeted for the treatment of type 2 diabetes, and have also shown promise for the treatment of neurodegenerative disease, including PD. Here, we tested the efficacy of glitazone administration during development in a fly GD model with deletions in the GBA homolog, dGBA1b (GBA1\u0394TT\/\u0394TT). We observed an optimal dose of pioglitazone (PGZ) at a concentration of 1 \u03bcM that reduced sleep deficits, locomotor impairments, climbing defects, and restoration of normal protein levels of Ref(2)P, a marker of autophagic flux, in GBA1\u0394TT\/\u0394TT mutant flies, compared to GBA1+\/+ control flies. These data suggest that PGZ may represent a potential compound with which to treat GD\/PD by improving function of lysosomal-autophagy pathways, a cellular process that removes misfolded or aggregated proteins.<\/jats:p>","DOI":"10.3390\/ijms222312740","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T04:48:37Z","timestamp":1638247717000},"page":"12740","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher\/Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"22","author":[{"given":"Oluwanifemi","family":"Shola-Dare","sequence":"first","affiliation":[{"name":"Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelby","family":"Bailess","sequence":"additional","affiliation":[{"name":"Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos C.","family":"Flores","sequence":"additional","affiliation":[{"name":"Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4124-8021","authenticated-orcid":false,"given":"William M.","family":"Vanderheyden","sequence":"additional","affiliation":[{"name":"Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3113-6974","authenticated-orcid":false,"given":"Jason R.","family":"Gerstner","sequence":"additional","affiliation":[{"name":"Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA"},{"name":"Steve Gleason Institute for Neuroscience, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,25]]},"reference":[{"key":"ref_1","first-page":"9","article-title":"Genetic risk factors in Parkinson\u2019s disease","volume":"373","author":"Billingsley","year":"2018","journal-title":"Z. Zellforsch. Mikrosk. Anat."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-019-0336-2","article-title":"Glucocerebrosidase and its relevance to Parkinson disease","volume":"14","author":"Do","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s00401-010-0741-7","article-title":"Glucocerebrosidase is present in \u03b1-synuclein inclusions in Lewy body disorders","volume":"120","author":"Stubblefield","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mcn.2015.03.013","article-title":"Glucocerebrosidase and Parkinson disease: Recent advances","volume":"66","author":"Schapira","year":"2015","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1093\/hmg\/ddu105","article-title":"Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice","volume":"23","author":"Xu","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1093\/brain\/awv040","article-title":"Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson\u2019s disease brain","volume":"138","author":"Roberts","year":"2015","journal-title":"Brain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/s41593-019-0423-2","article-title":"Lewy pathology in Parkinson\u2019s disease consists of crowded organelles and lipid membranes","volume":"22","author":"Shahmoradian","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1002\/ana.24781","article-title":"Specifically neuropathic Gaucher\u2019s mutations accelerate cognitive decline in Parkinson\u2019s","volume":"80","author":"Liu","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Stirnemann, J., Belmatoug, N., Camou, F., Serratrice, C., Froissart, R., Caillaud, C., Levade, T., Astudillo, L., Serratrice, J., and Brassier, A. (2017). A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020441"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1146\/annurev.genet.39.110304.095804","article-title":"Drosophila as a Model for Human Neurodegenerative Disease","volume":"39","author":"Bilen","year":"2005","journal-title":"Annu. Rev. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1242\/dmm.023762","article-title":"Drosophila tools and assays for the study of human diseases","volume":"9","author":"Ugur","year":"2016","journal-title":"Dis. Model. Mech."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1124\/pr.110.003293","article-title":"Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery","volume":"63","author":"Pandey","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"The modENCODE Consortium, Roy, S., Ernst, J., Kharchenko, P.V., Kheradpour, P., Negre, N., Eaton, M.L., Landolin, J.M., Bristow, C.A., and Ma, L. (2010). Identification of Functional Elements and Regulatory Circuits by Drosophila modENCODE. Science, 330, 1787\u20131797.","DOI":"10.1126\/science.1198374"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/ng2049","article-title":"Using FlyAtlas to identify better Drosophila melanogaster models of human disease","volume":"39","author":"Chintapalli","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Davis, M.Y., Trinh, K., Thomas, R.E., Yu, S., Germanos, A.A., Whitley, B.N., Sardi, S.P., Montine, T.J., and Pallanck, L.J. (2016). Glucocerebrosidase Deficiency in Drosophila Results in \u03b1-Synuclein-Independent Protein Aggregation and Neurodegeneration. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005944"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11654","DOI":"10.1523\/JNEUROSCI.4527-15.2016","article-title":"A Drosophila Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin","volume":"36","author":"Kinghorn","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.gene.2017.03.004","article-title":"Minos-insertion mutant of the Drosophila GBA gene homologue showed abnormal phenotypes of climbing ability, sleep and life span with accumulation of hydroxy-glucocerebroside","volume":"614","author":"Kawasaki","year":"2017","journal-title":"Gene"},{"key":"ref_18","first-page":"2712","article-title":"The contribution of mutantGBAto the development of Parkinson disease in Drosophila","volume":"25","author":"Maor","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1007\/s12035-012-8259-8","article-title":"Peroxisome Proliferator-Activated Receptor Gamma (PPAR-\u03b3) and Neurodegenerative Disorders","volume":"46","author":"Chen","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9030","DOI":"10.1038\/s41598-017-09702-3","article-title":"Pioglitazone Enhances Cytosolic Lipolysis, \u03b2-oxidation and Autophagy to Ameliorate Hepatic Steatosis","volume":"7","author":"Hsiao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.brainresbull.2011.03.011","article-title":"Protective effect of pioglitazone, a PPAR\u03b3 ligand, in a 3 nitropropionic acid model of Huntington\u2019s disease","volume":"85","author":"Napolitano","year":"2011","journal-title":"Brain Res. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.expneurol.2012.08.012","article-title":"In search of the neuroprotective mechanism of thiazolidinediones in Parkinson\u2019s disease","volume":"238","author":"Ridder","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4089214","DOI":"10.1155\/2017\/4089214","article-title":"Neuroprotective Effect and Mechanism of Thiazolidinedione on Dopaminergic Neurons In Vivo and In Vitro in Parkinson\u2019s Disease","volume":"2017","author":"Wang","year":"2017","journal-title":"PPAR Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1021\/acschemneuro.1c00085","article-title":"Glitazones Activate PGC-1\u03b1 Signaling via PPAR-\u03b3: A Promising Strategy for Antiparkinsonism Therapeutics","volume":"12","author":"Prabitha","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.2174\/1389557521666210304112403","article-title":"Glitazones, PPAR-\u03b3 and Neuroprotection","volume":"21","author":"Kumar","year":"2021","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1007\/s11064-014-1377-0","article-title":"PPAR\u03b3 and PGC-1\u03b1 as Therapeutic Targets in Parkinson\u2019s","volume":"40","author":"Corona","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.arr.2018.03.004","article-title":"PGC-1\u03b1 sparks the fire of neuroprotection against neurodegenerative disorders","volume":"44","author":"Lv","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/1742-2094-8-91","article-title":"The PPAR-\u03b3 agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys","volume":"8","author":"Swanson","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Brauer, R., Bhaskaran, K., Chaturvedi, N., Dexter, D.T., Smeeth, L., and Douglas, I. (2015). Glitazone Treatment and Incidence of Parkinson\u2019s Disease among People with Diabetes: A Retrospective Cohort Study. PLoS Med., 12.","DOI":"10.1371\/journal.pmed.1001854"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1002\/mds.27128","article-title":"Glitazone use associated with reduced risk of Parkinson\u2019s disease","volume":"32","author":"Brakedal","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1080\/07853890.2018.1488083","article-title":"Association of thiazolidinedione with a lower risk of Parkinson\u2019s disease in a population with newly-diagnosed diabetes mellitus","volume":"50","author":"Lin","year":"2018","journal-title":"Ann. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1111\/ene.14542","article-title":"Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus","volume":"28","author":"Chang","year":"2021","journal-title":"Eur. J. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nrn2683","article-title":"The genetic and molecular regulation of sleep: From fruit flies to humans","volume":"10","author":"Cirelli","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.expneurol.2012.08.018","article-title":"Circadian and sleep disorders in Parkinson\u2019s disease","volume":"243","author":"Videnovic","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Gerstner, J.R., Vanderheyden, W.M., Shaw, P.J., Landry, C.F., and Yin, J.C.P. (2011). Fatty-Acid Binding Proteins Modulate Sleep and Enhance Long-Term Memory Consolidation in Drosophila. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0015890"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1002\/jnr.23778","article-title":"Amyloid-\u03b2 induces sleep fragmentation that is rescued by fatty acid binding proteins in Drosophila","volume":"95","author":"Gerstner","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1093\/hmg\/ddu587","article-title":"PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43","volume":"24","author":"Joardar","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","first-page":"e52741","article-title":"Quantitative Analysis of Climbing Defects in a Drosophila Model of Neurodegenerative Disorders","volume":"10","author":"Madabattula","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_39","first-page":"e2504","article-title":"Assaying Locomotor, Learning, and Memory Deficits in Drosophila Models of Neurodegeneration","volume":"10","author":"Ali","year":"2011","journal-title":"J. Vis. Exp."},{"key":"ref_40","first-page":"a009357","article-title":"The Role of Autophagy in Parkinson\u2019s Disease","volume":"2","author":"Mao","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Zhu, Z., Yang, C., Iyaswamy, A., Krishnamoorthi, S., Sreenivasmurthy, S.G., Liu, J., Wang, Z., Tong, B.C.-K., Song, J., and Lu, J. (2019). Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson\u2019s Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030728"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3702","DOI":"10.2174\/0929867325666180226094351","article-title":"Role of Autophagy in Parkinson\u2019s Disease","volume":"26","author":"Cerri","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1016\/j.jmb.2020.01.037","article-title":"Autophagy in Parkinson\u2019s Disease","volume":"432","author":"Hou","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1756-6606-2-29","article-title":"The emerging role of autophagy in Parkinson\u2019s disease","volume":"2","author":"Cheung","year":"2009","journal-title":"Mol. Brain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1101\/pdb.prot080333","article-title":"Monitoring Autophagic Flux Using Ref(2)P, the Drosophila p62 Ortholog","volume":"2014","author":"DeVorkin","year":"2014","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"851","DOI":"10.3389\/fphar.2018.00851","article-title":"Pioglitazone Protects Against Renal Ischemia-Reperfusion Injury via the AMP-Activated Protein Kinase-Regulated Autophagy Pathway","volume":"9","author":"Chen","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"757","DOI":"10.3233\/JPD-202128","article-title":"Parkinson\u2019s Disease Drug Therapies in the Clinical Trial Pipeline: 2020","volume":"10","author":"McFarthing","year":"2020","journal-title":"J. Parkinson\u2019s Dis."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Church, F. (2021). Treatment Options for Motor and Non-Motor Symptoms of Parkinson\u2019s Disease. Biomolecules, 11.","DOI":"10.3390\/biom11040612"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1126\/science.287.5459.1834","article-title":"Correlates of Sleep and Waking in Drosophila melanogaster","volume":"287","author":"Shaw","year":"2000","journal-title":"Science"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/12740\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:35:40Z","timestamp":1760168140000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/12740"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,25]]},"references-count":49,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222312740"],"URL":"https:\/\/doi.org\/10.3390\/ijms222312740","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,25]]}}}