Modeling Neurofibrillary Degeneration
Progressive supranuclear palsy shares its defining pathologic signature, neurofibrillary tangles (NFT) consisting primarily of hyperphosphorylated tau, with numerous neurological diseases, including Alzheimer's disease, corticobasal degeneration, Pick's disease as well as frontotemporal dementia and Parkinsonism linked to chromosome 17. To improve our understanding of the mechanism underlying NFT formation and its functional impacts we have developed cellular models that produce tau filaments with morphological and biochemical characteristics of human tauopathies. The models consist of conditional transfectants generated from human neuroglioma [H4] and neuronal [BE(2)-M17D] cells in which transgenic production of wild-type or mutant tau is regulated via the TetOff inducible mechanism. Preliminary studies demonstrated that treatment of these cells with 4-hydroxynonneal (HNE), proteosomal or calpain inhibitors enhances the assembly of disulfide-linked tau aggregates. The results suggest that cellular insults such as oxidative stress and deregulation of proteases may play a role in the formation of NFT. We will employ this cellular model to uncover the molecular mechanism underlying tau aggregation induced by various insults.
The Specific Aims of our proposal are:
- To test if factors implicated in the etiology and pathogenesis of human tauopathies exacerbate tau aggregation in conditional transfectants,
- To determine if the enhanced aggregation is associated with changes in tau solubility/partition, phosphorylation, degradation and oligomerization,
- To investigate whether such exacerbated tau aggregation is associated with altered level or state of activation/activity of particular kinases, proteases and/or proteasomes, and
- To study if progression of the exacerbated assembly of tau aggregates can be blocked through deregulating kinases/proteases. The results are likely to provide valuable information for a rational design of therapeutics to treat neurofibrillary degeneration.