Parkin protection in gene transfer animal models (KO-1 Award)

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DESCRIPTION (provided by applicant): Protein aggregation comprises an important pathological landmark in Parkinson's disease [PD], Alzheimer's disease [AD] and the tauopathies with Parkinsonism. Parkin is an E3 ubiquitin-ligase involved in the proteasomal degradation of misfolded proteins. Loss of parkin's E3 ubiquitin-ligase function is associated with early onset Parkinsonism. Accumulation of amyloid proteins, including a-synuclein in PD and ¿-amyloid in AD, is the initiating step in their respective disease progression. Several proteins, including a-synuclein, are known to be targets of parkin ubiquitin-ligase activity. Preliminary data show for the first time that wild type parkin decreases the steady-state levels of intracellular A¿42, raising the possibility that intracellular ¿-amyloid is also a target for the ubiquitin-ligase activity of parkin. Both A¿ and a-synuclein deposits variably co-exist with tau in certain overlapping neurodegenerative diseases with dementia and Parkinsonism, however, it is not known how either of them interacts with tau to provoke neurofibrillary tangle formation across the tauopathies. Preliminary data show that wild type parkin attenuates tau combined with either a-synuclein or ¿-amyloid toxicity in human neurblastoma SH-SY5Y cells, but fails to significantly decrease tau toxicity alone. Therefore, parkin may reduce intracellular a-synuclein and ¿-amyloid levels, thus preventing them from forming "amyloid templates" that trigger tau modification in cell culture and animal models in vivo. Parkin rescues cells from intracellular A¿42 and a-synuclein toxicity as well as mitochondrial toxins-induced stress, and these effects are concurrent with decreased amyloid levels and increased proteasome activity. This research is expected to show that parkin is capable of restoring amyloid-induced mitochondrial ATP energy deficits, which affect proteasome activity to prevent toxic accumulation of proteins. I will generate gene transfer animal models to investigate the role of parkin to decrease the level of amyloid 'templates', counteracting their toxic effects on the mitochondria and alteration of tau metabolism in the spectrum of syndromes with tau cytopathy and Parkinsonism. These studies may provide a potential double-pronged therapeutic strategy involving parkin as an E3 ubiquitin-ligase to reduce intracellular protein accumulation, and mitochondrial protectant capable of restoring ATP energy levels, in the spectrum of neurodegenerative diseases with dementia and Parkinsonism.