Preclinical Evaluation of Celastrol, an Inducer of HSP, in alpha-Syn Tg mice

描述(申请人提供)：虽然帕金森病的病因尚不清楚，但a-突触核蛋白(a-Syn)的遗传和生化异常直接与帕金森病和其他a-突触核病的发病机制有关。我们已经证明，使用鼠普恩蛋白启动子(MPRP)而不是野生型(WT)或A30P表达A53T突变的人α-Syn的转基因(TG)小鼠，会发展成成人起病，并导致进行性运动功能障碍导致死亡。受影响的小鼠表现出许多人类a-突触核病的特征，包括a-syn的纤维聚集和神经变性。虽然a-突触核病的发病机制目前尚未确定，但大量研究表明，调节细胞蛋白伴侣可以改变与a-Syn表达/聚集相关的毒性。特别是，热休克蛋白水平的增加可以保护果蝇模型α-突触核病模型中α-Syn依赖性变性的神经元。因此，药物诱导细胞伴侣蛋白的表达可能对a-突触核病有治疗作用。HSP的药理学诱导延缓了SOD1转基因ALS小鼠模型的疾病进展，这一事实支持了这一理论。近年来，从卫矛科植物中提取的天然产物水芹醇被证明是HSF-1和HSP表达的强效激活剂。我们将测试雷公藤红素是否可以调节表达A53T突变型华精蛋白的转基因(TG)小鼠的α-突触核病和帕金森病慢性MPTP模型中的多巴胺能变性。这项研究将为体内a-突触核变性的发病机制提供有价值的机制见解。更重要的是，我们希望为进一步筛选和测试其他能够诱导HSP表达的化合物作为治疗a-突触核病的潜在治疗药物提供有力的依据。帕金森病和相关的阿尔法突触核病是致命的神经退行性疾病，每年在美国影响50万至100万人。目前，还没有减缓或阻止这些疾病发展的治疗方法。在过去的几年中，研究表明α-突触核蛋白的遗传和生化异常与帕金森病的发病有关。体外研究和对α-突触核蛋白依赖性神经变性苍蝇模型的研究表明，热休克调节的伴侣蛋白表达增加可以提供神经保护，使其免受α-突触核蛋白异常的神经毒性影响。我们将通过给予新型化合物雷公藤红素来确定热休克蛋白的增加是否可以防止与帕金森病直接相关的哺乳动物动物模型的神经退行性变。

DESCRIPTION (provided by applicant): While the causes of Parkinson's disease is not known, genetic and biochemical abnormalities of a-synuclein (a-Syn) are directly implicated in the pathogenesis PD and other a-synucleinopathies. We have shown that transgenic (Tg) mice expressing the A53T mutant human a-Syn using the mouse prion protein promoter (mPrP), but not wild type (WT) or A30P, develop adult-onset disease with a progressive motoric dysfunction leading to death. The affected mice exhibit many features of human a-synucleinopathies, including fibrillar aggregation of a-Syn and neurodegeneration. While the pathogenic mechanisms of a-synucleinpathy is current not settled, number of studies indicate that modulation of cellular protein chaperones can alter toxicity associated with a-Syn expression/aggregation. In particular, increased levels of heat shock protein can protect neurons for a-Syn-dependent degeneration in the Drosophila model a-synucleinopathy. Thus, pharmacological induction of cellular chaperone expression could be therapeutic benefit for a-synucleinopathy. This rationale is supported by the fact that the pharmacological induction of HSP delays disease progression in SOD1 transgenic mouse model of ALS. Recently, Celasterol, a natural product derived from the Celastraceae family of plants, has been shown to be a potent activator or HSF-1 and HSP expression. We will test whether Celastrol can modulate a-synucleinopathy in the Transgenic (Tg) mice expressing the A53T mutant Hua-Syn and Dopaminergic degeneration in a chronic MPTP model of PD. The study will provide valuable mechanistic insights about the pathogenesis of a-synucleinopaty in vivo. More important, we hope to provide a strong rational for further screening and testing of other compounds that can induce HSP expression as potential therapeutic agents for treating a-synucleinopathy. Parkinson's Disease and related alpha-synucleinopathies are fatal neurodegenerative diseases affecting 500,000-1,000,000 individuals annually in US. Currently, there are no treatment to slow or halt the progression of these diseases. In the last several years, studies have implicated genetic and biochemical abnormalities of alpha-synuclein in the pathogenesis of PD. In vitro studies and studies in a fly model of alpha-synuclein dependent neurodegeneration suggest that increased expression of heat shock regulated chaperones could provide neuroprotection from the neurotoxic effect of alpha-synuclein abnormalities. We will determine whether increase in heat shock proteins, via administration of novel compound celastrol, can prevent neurodegeneration in mammalian animal models that are directly relevant to PD.