The neuronal microtubule associated protein tau is a substrate for caspase-3 and an effector of apoptosis

Fasulo, Luisa; Ugolini, Gabriele; Visintin, Michela; Bradbury, Andrew; Verzillo, Vittorio; Novák, Michal; Cattaneo, Antonino

doi:10.1016/s0197-4580(00)82181-8

Cited by 48 publications

(59 citation statements)

References 43 publications

(38 reference statements)

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“…Subsequently, the precise site in tau polypeptide cleaved by activated caspase 3 was identified as Asp 421 [49]. Finally, the presence of this caspase-cleavage product of tau in AD brains was also confirmed by TauC3 and α-Tau antibodies [8,11].…”

Section: Tau Truncation In Ad: From Discovery To Therapymentioning

confidence: 82%

The self-perpetuating tau truncation circle

Žilka

Kováčech

Baráth

et al. 2012

Biochemical Society Transactions

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Pathological truncations of human brain proteins represent the common feature of many neurodegenerative disorders including AD (Alzheimer's disease), Parkinson's disease and Huntington's disease. Protein truncations significantly change the structure and function of these proteins and thus can engender their pathological metamorphosis. We have shown previously that truncated forms of tau protein are contained in the core of the paired helical filaments that represent the main constituent of neurofibrillary pathology. Recently, we have identified truncated tau species of a different molecular signature. We have found that tau truncation is not produced by a random process, but rather by highly specific proteolytic cleavage and/or non-enzymatic fragmentation. In order to characterize the pathophysiology of AD-specific truncated tau species, we have used a transgenic rat model for AD expressing human truncated tau. Expression of the tau protein induces the formation of novel truncated tau species that originate from both transgenic human tau and endogenous rat tau proteins. Moreover, these truncated tau proteins are found exclusively in the misfolded fraction of tau, suggesting that they actively participate in the tau misfolding process. These findings corroborate further the idea that the appearance of truncated tau species starts a self-perpetuating cycle of further tau protein truncation leading to and accelerating tau misfolding and formation of neurofibrillary pathology.

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Section: Tau Truncation In Ad: From Discovery To Therapymentioning

confidence: 82%

The self-perpetuating tau truncation circle

Žilka

Kováčech

Baráth

et al. 2012

Biochemical Society Transactions

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“…Several known hits including Tpx2 (Xenopus kinesin-like protein 2), Mapt (microtubule associated protein tau), Brca1 (breast cancer 1, early onset), Apc (adenomatous polyposis coli) and CryAB (alpha-crystallin B chain) were found to be up-regulated in data and observed in modulating the apoptotic process (Fasulo et al, 2000;Shao et al, 1996;Chis et al, 2012;Moss et al, 2009;Dikovskaya et al, 2007). Quite interestingly, Tcte3 and Anxa5 were detected in intersection data set.…”

Section: Discussionmentioning

confidence: 98%

“…5BII). However, CryAB, Mapt (Fasulo et al, 2000), (Steigerwald et al, 2005), Brca1 (Shao et al, 1996) and Tpx2 (Chang et al, 2012) were common genes for both processes which are involved in regulating the induction of cell death, inhibition of mitosis, cell cycle control and/or induction of cellular differentiation ( (Fig. 5B), purple circle).…”

Section: Isolation Of Modules Correlated With Microtubule and Apoptosmentioning

confidence: 99%

Disruption of murine Tcte3-3 induces tissue specific apoptosis via co-expression of Anxa5 and Pebp1

Parveen¹,

Bibi²,

Bibi³

et al. 2014

Computational Biology and Chemistry

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“…Caspase-3, a cysteine protease, is in fact a key enzyme in cell apoptosis and it has been proved to be directly involved in the neurodegeneration of the Alzheimer×s disease [49]. Up to now research of caspase-3 inhibitors has been based only on combinatorial chemistry that, however, has not completely solved efficiency and selectivity problems.…”

Section: Towards the Development Of A Transition Statementioning

confidence: 99%

“…We focus on a class of cysteine proteases, the caspases. These enzymes are extremely important targets for pharmaceutical intervention in therapies against Alzheimer×s and other neurodegenerative processes [49], yet very few inhibitors have been so far designed. This work provides important insights for the development of caspase-3 specific transition state analog inhibitors [50,51].…”

Section: Introductionmentioning

confidence: 99%

Applications of Density Functional Theory-Based Methods in Medicinal Chemistry

Sulpizi

Folkers²,

Röthlisberger

et al. 2002

Quant. Struct.-Act.Relat.

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With the advances in genomics, proteomics and functional genomics new therapeutic targets to be tackled by medicinal chemistry are expected. This article reviews applications of first principle methods to address medicinal chemistry issue related to drug/target interactions. Two selected representative case studies involving therapeutically interesting targets are presented. The first case study presents how DFT can contribute to ameliorate scoring functions for drug screening in particular by enabling the discrimination between inhibitors and substrates. The second example shows the use of DFT within the framework of a QM/MM mixed approach for elucidating mechanisms of reaction. This approach allows defining the electronic state and structure of the reaction transition state whose knowledge is essential for designing potent and specific transition state analogs inhibitors. Finally, addressing the issue of other medicinal chemistry related application of DFT we suggest that DFT has indeed the potentiality of becoming very important for challenging new issues presented to medicinal chemistry in the post genomic era.

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The neuronal microtubule associated protein tau is a substrate for caspase-3 and an effector of apoptosis

Cited by 48 publications

References 43 publications

The self-perpetuating tau truncation circle

The self-perpetuating tau truncation circle

Disruption of murine Tcte3-3 induces tissue specific apoptosis via co-expression of Anxa5 and Pebp1

Applications of Density Functional Theory-Based Methods in Medicinal Chemistry

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