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

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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.