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

雷公藤红醇（HSP 诱导剂）在 α-Syn Tg 小鼠中的临床前评估

• 批准号: 7257686
• 负责人: MICHAEL K LEE
• 金额: $ 21.51万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257686
• 关键词: Acute; Adult; Affect; Alpha-Synuclein transgenic mouse; Amyotrophic Lateral Sclerosis; Animal Model; Attenuated; Biochemical Genetics; Biological Factors; Brain; Celastraceae; Cells; Cessation of life; Chronic; Cultured Cells; Disease Progression; Dose; Drosophila genus; Evaluation; Exhibits; Family; Functional disorder; Heat shock proteins; Heat-Shock Proteins 70; Heat-Shock Response; Human; In Vitro; Individual; Modeling; Molecular Chaperones; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Numbers; Onset of illness; Parkinson Disease; Pathogenesis; Pathway interactions; Plants; Prions; Protein Family; Proteins; Screening procedure; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Transgenic Organisms; Treatment Efficacy; UC01; alpha synuclein; cohort; dopaminergic neuron; fly; in vivo; insight; late disease onset; member; mouse model; multicatalytic endopeptidase complex; mutant; neuroprotection; neurotoxic; novel; pre-clinical; prevent; promoter; response; synuclein; transcription factor; tripterine

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.

描述（由申请人提供）：虽然帕金森病的病因尚不清楚，但α-突触核蛋白（a-Syn）的遗传和生化异常与帕金森病和其他α-突触核蛋白病的发病机制直接相关。我们已经证明，使用小鼠朊病毒蛋白启动子（mPrP）而非野生型（WT）或A30P表达A53T突变型人类α-Syn的转基因（Tg）小鼠会发展成成人发病的疾病，并伴有进行性运动功能障碍，导致死亡。受影响的小鼠表现出人类α-突触核蛋白病的许多特征，包括α-Syn的纤维聚集和神经变性。虽然α-突触核蛋白病的致病机制目前尚未确定，但大量研究表明细胞蛋白伴侣的调节可以改变与α-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-突触核蛋白病中神经元的α-Syn依赖性变性。因此，细胞伴侣表达的药理学诱导可能对α-突触核蛋白病具有治疗益处。这一基本原理得到了以下事实的支持：在 ALS 的 SOD1 转基因小鼠模型中，HSP 的药理诱导可延缓疾病进展。最近，雷公藤醇（一种源自卫矛科植物的天然产物）已被证明是 HSF-1 和 HSP 表达的有效激活剂。我们将测试雷公藤红素是否可以调节表达 A53T 突变体 Hua-Syn 的转基因 (Tg) 小鼠中的 a-突触核蛋白病和 PD 慢性 MPTP 模型中的多巴胺能变性。该研究将为体内α-突触核病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可诱导 HSP 表达的化合物作为治疗 α-突触核蛋白病的潜在治疗剂提供有力的依据。帕金森病和相关的 α-突触核蛋白病是致命的神经退行性疾病，每年影响美国 500,000-1,000,000 人。目前，没有治疗方法可以减缓或阻止这些疾病的进展。在过去几年中，研究表明 α-突触核蛋白的遗传和生化异常与 PD 的发病机制有关。体外研究和α-突触核蛋白依赖性神经变性果蝇模型的研究表明，热休克调节伴侣的表达增加可以提供神经保护，免受α-突触核蛋白异常的神经毒性作用。我们将确定通过施用新型化合物雷公藤红素增加热休克蛋白是否可以预防与帕金森病直接相关的哺乳动物模型中的神经变性。