Neurofibrillary tangles (NFTs), made up of abnormally aggregated tau protein, are found in Alzheimer's disease (AD), a familial form of Parkinson's disease (PD) and other neurodegenerative diseases such as progressive supranuclear palsy (PSP), cortico-basal degeneration (CBD) and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The NFTs are often found in the substantia nigra (SN). Degeneration of the substantia nigra causes Parkinsonism in PD, PSP, CBD and FTDP-17. For these reasons, we expressed a disease-related form of tau (P301L) in the rat SN using the adeno-associated virus (AAV) vector. The tau gene transfer resulted in a significant model of SN degeneration as described in the preliminary results, with NFT formation, loss of SN dopamine neurons, reduced striatal dopamine, and amphetamine-stimulated rotational behavior, using high doses of the P301L tau vector. We will now compare P301L with wild-type (wt) tau at several doses and time points, because the vast majority of NFT diseases involve wt tau. Vector dose-response will establish consistent/controllable expression levels. Time course studies will establish rates of pathogenesis. A unique twist of the vector approach is controlling the onset of expression. We will utilize this feature to test whether the aged brain is more susceptible to tau-related neurodegenerative damage by expressing P301L tau under similar conditions in either young or old animals. Because the P301L tau-induced disease state is still relatively weak compared to standard 6- hydroxydopamine (6-OHDA) lesions, we will investigate potential enhancements including different forms of the AAV vector (serotypes 5 and 8 in addition to the routinely used serotype 2), and coupling alpha-synuclein (alpha-synuclein ) expression with tau. The long-term goals are to test drug therapies in live animals which have stable deficits in motor behavior and in brain imaging with dopaminergic probes. The more efficient vectors may enhance the stability of the disease state for future drug studies. Co-expression of tau with several other proteins including molecular chaperones will address mechanisms involved in tau-induced neurodegeneration. There is evidence that a-synuclein, hsp70, CHIP, parkin and pinl may interact with tau. In coexpression studies, we hypothesize that: 1) alpha-synuclein will modulate tau filament formation and produce a unique disease state; 2) hsp70 will degrade tau and be neuroprotective; 3) CHIP will ubiquitinate tau and increase levels of insoluble tau and be neuroprotective; 4) parkin will ubiquitinate tau and be neuroprotective; and 5) pinl will dephosphorylate tau and be neuroprotective. The overall Aim is to use an antagonist blocker strategy to target a specific mechanism that could then be developed with small molecules or even gene therapy, the latter perhaps being a rational option based on the lack of drugs for these pernicious diseases.
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