Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson's Disease.
Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson's Disease.
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DOI：
10.3390/ijms222312740
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发表时间：
2021-11-25
影响因子：
5.6
通讯作者：
Gerstner JR
中科院分区：
文献类型：
--
作者：
Shola-Dare O;Bailess S;Flores CC;Vanderheyden WM;Gerstner JR
帕金森氏病(PD)是最常见的运动障碍，而PD最强的遗传风险因素是葡萄糖脑苷酶基因(GBA)的突变。GBA的突变也会导致高谢病(GD)的发展，这是最常见的溶酶体储存障碍类型。目前的治疗方法不能解决神经性GD症状。因此，在动物模型中找出改善与GD/PD相关的表型特征的治疗策略可能为治疗GD/PD的神经学表现提供机会。噻唑烷二酮(TZDS，又称格列酮)是一类针对2型糖尿病的化合物，也显示出在治疗包括帕金森病在内的神经退行性疾病方面的希望。在这里，我们在GbA同源基因dGBA1b(GBA1ΔTT/ΔTT)缺失的果蝇GD模型上测试了格列酮在发育过程中的疗效。与μ+/+对照果蝇相比，我们观察到最佳剂量的吡格列酮(PGZ)在1 GbA1 M的浓度下可以减少ΔTT/ΔTT突变果蝇的睡眠不足、运动障碍、攀登缺陷以及恢复REF(2)P的正常蛋白水平。这些数据表明，PGZ可能是一种潜在的化合物，通过改善溶酶体-自噬途径的功能来治疗GD/PD，溶酶体-自噬途径是一种去除错误折叠或聚集的蛋白质的细胞过程。
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.
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