The Neuronal Microtubule‐Associated Protein Tau Is a Substrate for Caspase‐3 and an Effector of Apoptosis

Abstract

Abstract:We have identified a class of tau fragments inducing apoptosis in different cellular contexts, including a human teratocarcinoma-derived cell line (NT2 cells) representing committed human neuronal precursors. We have found a transition point inside the tau molecule beyond which the fragments lose their ability to induce apoptosis. This transition point is located around one of the putative caspase-3 cleavage sites. This is the only site that can be effectively used by caspase-3 in vitro, releasing the C-terminal 19 amino acids of tau. These results establish tau as a substrate for an apoptotic protease that turns tau itself into an effector of apoptosis. Accordingly, tau may be involved in a self-propagating process like what has been predicted for the pathogenesis of different neurodegenerative disorders. Key Words: Microtubule -Tau-Apoptosis-Caspase-3. J. Neurochem. 75, 624 -633 (2000).Proteolysis of cellular proteins is one of the critical mechanisms of apoptosis (Salvesen and Dixit, 1997). Although many protein substrates for apoptosis-activated proteases have been identified, their functional significance is poorly understood. Some of these substrates are cytoskeletal proteins, for example, actin, fodrin, gelsolin, and GAS2 (Brancolini et al

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

“…In fact, the overexpression of tau (1-230) as well as full-length tau actually protected CGNs from apoptotic death ( Figure 5-7). This finding is apparently in contrast with previous reports regarding the proapoptotic effect of the prolin-rich region within the N-terminal tau domain, 16 but the different types of cellular models and experimental manipulations may be the basis of such discrepancy. Thus, the proapoptotic action was observed in cyclic non-neuronal cells, while the antiapoptotic effect that we found was in primary cultures of postmitotic neurons.…”

“…Moreover, the incomplete overlapping of the plasmids used to test the effect of tau on survival may add variances in the interpretation of the different results. In fact, the proapoptotic effect reported by Fasulo et al 16 was observed with a region of tau containing P1-P2 and R1, and lacking all the first 151 amino acids (tau (151-274)). In contrast, in our tau (1-230) construct R1 was absent and P2 was deleted from the last 12 aminoacids in which, for example, a functional SH3-binding domain is present.…”

“…Studies from different 'in vitro' models of neuronal apoptosis as well as from AD samples suggest that proteases activated during apoptosis may cause tau truncation. It has been reported, for example, that tau is cleaved by caspase-3 in its C-terminal domain, [15][16][17] while studies on AD samples have reported that caspases cleave the N-terminal tau domain, 18 and that this event may precede the aggregation of tau into neurofibrillary tangles (NTF). Moreover, transfection of neuronal cells with C-terminal caspase-3 generated tau fragment 16,17 and with different fragments encompassing its C-terminal domain 17 induces cell death, suggesting that truncated forms of tau can operate as toxic agents of a selfpropagating intracellular process of neuronal death.…”

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

“…Because of these differences, it is argued that human Tau, but not murine Tau, can exert neurotoxic effects. However, this hypothesis is contrasted by data showing that endogenous mouse Tau is required for Aβ-induced postsynaptic dysfunction and behavioral defects, [17][18][19][20][21][22][23][24] which suggest that murine Tau can carry out pathogenic functions that resemble that of human Tau AD.…”

“…20 Tau is cleaved at Aspartate 421 (D 421 ) by caspases into two peptides. Although the short COOH-terminal Tau peptide has not been the subject of investigation, the NH2-terminal Tau fragment, called δTau, has been extensively analyzed.…”