During apoptosis the cytoskeleton of the cell undergoes dynamic alterations which result in the characterisitic morphological changes common to most apoptotic cells. Recently, using the classical paradigm of inducing apoptosis differentiated PC12 cells by withdrawal of serum and nerve growth factor (NGF), we demonstrated that the neuronal cytoskeletal protein tau is hyperphosphorylated at specific epitopes during apoptosis. Further, there are associated functional changes, as the microtubule-bindng capacity of tau from apoptotic cells is significantly reduced, and it is restored after dephosphorylation. This demonstrates directly that the increased phosphorylation of tau in cells undergoing apoptosis impairs the function of tau, and thus may contribute to the microtubule instability and the cytoskeletal based morphological changes of apoptotic cells. These findings are exciting both for the insight they provide for understanding the drastic morphological changes associated with apoptosis, and for the potential links between apoptosis in Alzheimer's disease and hyperphosphorylated tau. There is increasing evidence that apoptotic-like processes may contribute to the neuronal death in Alzheimer's disease, as well as other neurodegenerative disorders. In Alzheimer's disease brain, extensively hyperphosphorylated tau forms paired helical filaments (PHFs). In addition, the microtubule binding of PHF-tau is impaired, but can be restored at least partially by dephosphorylation. Thus, apoptosis during Alzheimer's disease may contribute to the formation of hyperphosphorylated tau that accumulated in this disease, thereby further emphasising the need to clarify the mechanisms that control tau phosphorylation in these conditions. In AD brain, cdc2, casein kinase1d (CK1d ) and cdk5 are elevated, and the investigators have found them to be increased during apoptosis as well. Considering these and other findings, the comprehensive working hypothesis is that during apoptosis tau is hyperphosphorylated at specific sites by specific protein kinases and this hyperphosphorylation results in compromised tau function, which contributes to the structural changes that occur during apoptosis. Elucidation of the changes in tau phosphorylation that occur during apoptosis will contribute towards the understanding of the processes that result in the hyperphosphorylation of tau in AD and other neurodegenerative disorders.
The specific aims of this proposal are to test the hypotheses that: (1) during apoptosis tau is phosphorylated at specific sites and the increases in the activities of cdc2, CK1d and cdk5 are essential components of this process, (2) that the specific sites on tau that are phosphorylated in apoptotic cells modulate tau function and localization, and (3) that during apoptosis, tau with frontal temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) mutations is differentially phosporylated and localized compared to wild type tau.
Showing the most recent 10 out of 20 publications
