Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson's Disease

• Published in: International journal of molecular sciences 2021-11, Vol.22 (23), p.12740
• Main Authors: Shola-Dare, Oluwanifemi, Bailess, Shelby, Flores, Carlos C, Vanderheyden, William M, Gerstner, Jason R
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animal models; Animals; Autophagy; dementia; Diabetes mellitus (non-insulin dependent); Drosophila melanogaster; Drug dosages; Enzymes; Gaucher Disease - drug therapy; Gaucher Disease - etiology; Gaucher Disease - pathology; Gaucher's disease; Glucose; Glucosylceramidase; Glucosylceramidase - deficiency; Health risk assessment; Homology; Humans; Insects; Lewy body; Male; Mutation; Neurodegeneration; p62; Parkinson Disease - drug therapy; Parkinson Disease - etiology; Parkinson Disease - pathology; Parkinson's disease; Phagocytosis; Phenotype; Pioglitazone; Proteins; Risk analysis; Risk factors; Signs and symptoms; Sleep; Thiazolidinediones; Thiazolidinediones - pharmacology; β-acid glucosidase 1
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222312740

Parkinson's Disease (PD) is the most common movement disorder, and the strongest genetic risk factor for PD is mutations in the glucocerebrosidase gene ( ). Mutations in 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 homolog, ). 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 mutant flies, compared to 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.