Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson’s Disease
| Autor: | William M. Vanderheyden, Jason R. Gerstner, Shelby Bailess, Carlos C. Flores, Oluwanifemi Shola-Dare |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
autophagy Parkinson's disease QH301-705.5 Disease Type 2 diabetes Pharmacology Catalysis Article Inorganic Chemistry medicine Dementia Animals Humans Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Spectroscopy Gaucher Disease Lewy body business.industry Organic Chemistry Neurodegeneration p62 neurodegeneration Parkinson Disease General Medicine medicine.disease Computer Science Applications β-acid glucosidase 1 Chemistry Drosophila melanogaster Phenotype Glucosylceramidase Thiazolidinediones business Pioglitazone Glucocerebrosidase dementia medicine.drug |
| Zdroj: | International Journal of Molecular Sciences; Volume 22; Issue 23; Pages: 12740 International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 12740, p 12740 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms222312740 |
| Popis: | Parkinson’s 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 (GBA1ΔTT/ΔTT). We observed an optimal dose of pioglitazone (PGZ) at a concentration of 1 μM that reduced sleep deficits, locomotor impairments, climbing defects, and restoration of normal protein levels of Ref(2)P, a marker of autophagic flux, in GBA1ΔTT/ΔTT 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. |
| Databáze: | OpenAIRE |
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