"In this proposal, we hypothesize that RTP801, a neuron-death associated protein, is a target for parkin in cellular and animal models of Parkinson's disease (PD). We will test whether parkin regulates the proteasomal degradation of RTP801 and whether parkin loss of function elevates RTP801 to mediate neuron death in cellular and animal models of PD. RTP801 is elevated in cell and animal models of PD and in affected neurons of PD patients. In PD models, RTP801 up regulation leads to inactivation of mTOR and Akt, and therefore neuron death. Parkin is a PD-associated gene that, when mutated, triggers juvenile recessive-autosomal forms of PD. Controversially, mutations in only one allele of parkin gene can be a risk factor for Parkinsonism. Our preliminary results suggest that RTP801 is degraded by the ubiquitin proteasome system and that parkin impairment leads to RTP801 accumulation in vitro. We will investigate whether parkin loss of function triggers toxic accumulation of RTP801 at a transcriptional level and/or at the protein level, due to degradation impairment. We will analyze the toxicity of different parkin mutations and if so, whether they induce cell death through RTP801. In this context, we will also investigate whether the mTOR /Akt survival pathway is impaired. Moreover we will investigate whether mutant Parkin -Q311X mice show RTP801 accumulation in the Substantia Nigra (SN). Finally, and if available, we will explore the levels of RTP801 in human tissue from patients with several parkin mutations to see if the samples exhibit elevated levels of RTP801 in the affected neuromelanin neurons in the SN. The final goal of these experiments will be a better understanding of neural degeneration in the disease and will help to design effective therapeutic approaches to treat neural degeneration in PD."
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