Ser422 phosphorylation blocks human Tau cleavage by caspase-3: Biochemical implications to Alzheimer’s Disease

Sandhu, Priya; Naeem, Mansur Mohammad; Lu, Chunyu; Kumarathasan, Premkumari; Gomes, James; Basak, Ajoy

doi:10.1016/j.bmcl.2016.11.087

Cited by 17 publications

(16 citation statements)

References 68 publications

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“…The seemingly protective effects of tau truncation at D421 raises the question of what kind of underlying mechanism for this proteolysis to neutralize hyperphosphorylation-induce toxicity might be. Indeed, the effect of interactions between different PTMs is a challenging question for which little evidence is available 18 , 63 . In terms of the relationship between phosphorylation and truncation, while the proteolytic cleavage at D421 has been considered an early event preceding phosphorylation 25 , a study on the temporal sequence of tau PTMs revealed that tau phosphorylation occurs before proteolytic cleavage at D421 21 .…”

Section: Discussionmentioning

confidence: 99%

“…The modulation of cdk5/p35 kinase did not impact human tau toxicity in a Drosophila model 15 , and a confounding study showed that the expression of mitogen-activated protein kinase p38γ could ameliorate tau toxicity through the phosphorylation of T205, a site that is also targeted by GSK-3β 14 . Therefore, whether tau hyperphosphorylation exerts cytotoxic effects remains an open question 14 – 18 .…”

Section: Introductionmentioning

confidence: 99%

“…However, a study of tau transgenic mice showed that while caspase activation generates tau-D421-cleaved variant and tangle formation, those neurons remain alive 25 . Importantly, neurons exhibited truncated tau also showed increased phospho-epitope labeling 25 , suggesting the interaction of these two modes of PTM impact tau toxicity 18 , 26 .…”

Section: Introductionmentioning

confidence: 99%

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Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

Ran

Sun

Shiu

et al. 2020

Sci Rep

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Hyperphosphorylated and truncated tau variants are enriched in neuropathological aggregates in diseases known as tauopathies. However, whether the interaction of these posttranslational modifications affects tau toxicity as a whole remains unresolved. By expressing human tau with disease-related Ser/Thr residues to simulate hyperphosphorylation, we show that despite severe neurodegeneration in full-length tau, with the truncation at Asp421, the toxicity is ameliorated. Cytological and biochemical analyses reveal that hyperphosphorylated full-length tau distributes in the soma, the axon, and the axonal terminal without evident distinction, whereas the Asp421-truncated version is mostly restricted from the axonal terminal. This discrepancy is correlated with the fact that fly expressing hyperphosphorylated full-length tau, but not Asp421-cleaved one, develops axonopathy lesions, including axonal spheroids and aberrant actin accumulations. The reduced presence of hyperphosphorylated tau in the axonal terminal is corroborated with the observation that flies expressing Asp421-truncated variants showed less motor deficit, suggesting synaptic function is preserved. The Asp421 cleavage of tau is a proteolytic product commonly found in the neurofibrillary tangles. Our finding suggests the coordination of different posttranslational modifications on tau may have an unexpected impact on the protein subcellular localization and cytotoxicity, which may be valuable when considering tau for therapeutic purposes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

Ran

Sun

Shiu

et al. 2020

Sci Rep

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“…As mentioned above, D421-truncated tau can be found in AD brains, and this cleaved form is suspected to facilitate tau aggregate formation and thus enhancing the toxicity [124,129,133,134]. Phosphorylation at S422 could prevent the truncation, which could be mediated by JNK and TTBK-1 [114,135,136]. Nevertheless, JNK and TTBK-1 could also phosphorylate tau at the sites other than S422, which complexes the protective scenario [114,136].…”

Section: Caspasesmentioning

confidence: 97%

Tauopathy

Ran¹,

Sang²,

Chang³

2019

Cognitive Disorders

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Tauopathy is a category of neurodegenerative diseases that are caused or associated with pathological tau protein. Some of the diseases are relatively common, which include Alzheimer's disease (AD) and various Parkinsonism (PD). Tau protein is a type of microtubule-associated protein (MAP), encoded by the gene MAPT (microtubule-associated protein tau). Normally, tau binds to microtubule, supporting the assembling and structure of cytoskeletons. However, in tauopathy, normal tau protein undergoes abnormal posttranslational modifications and detaches from microtubule; furthermore, they may aggregate forming paired helical filaments (PHF) or straight filaments (SF). Abundant PHF could be observed under microscope as fibrillary tangles. In this chapter, we will introduce the pathogenesis process of tauopathy with regard to the posttranslational modifications of the protein, the animal models, and the developing treatments against tauopathy from a clinical prospective.

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“…Several caspases, including caspase-3 can cleave tau at Asp421 (Jarero- Basulto et al, 2013). Interestingly, in peptides containing the proposed caspase-3 cleavage region, phosphorylation of neighbouring Ser422 brings resistance to truncation (Sandhu et al, 2017). Thus, although it is generally considered that phosphorylation favours tau aggregation, it is possible that phosphorylation at some specific sites may be protective.…”

Section: Tau Truncation In Admentioning

confidence: 99%

The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease

Jembrek

Slade

Hof

et al. 2018

Progress in Neurobiology

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Alzheimer's disease (AD), the most common progressive neurodegenerative disorder, is characterized by severe cognitive decline and personality changes as a result of synaptic and neuronal loss. The defining clinicopathological hallmarks of the disease are deposits of amyloid precursor protein (APP)-derived amyloid-β peptides (Aβ) in the brain parenchyma, and intracellular aggregates of truncated and hyperphosphorylated tau protein in neurofibrillary tangles (NFT). At the cellular and molecular levels, many intertwined pathological mechanisms that relate Aβ and tau pathology with a transcription factor p53 have been revealed. p53 is activated in response to various stressors that threaten genomic stability. Depending on damage severity, it promotes neuronal death or survival, predominantly via transcription-dependent mechanisms that affect expression of apoptosis-related target genes. Levels of p53 are enhanced in the AD brain and maintain sustained tau hyperphosphorylation, whereas intracellular Aβ directly contributes to p53 pool and promotes downstream p53 effects. The review summarizes the role of p53 in neuronal function, discusses the interactions of p53, tau, and Aβ in the normal brain and during the progression of AD pathology, and considers the impact of the most prominent hereditary risk factors of AD on p53/tau/Aβ interactions. A better understanding of this intricate interplay would provide deeper insight into AD pathology and might offer some novel therapeutic targets for the improvement of treatment options. In this regard, drugs and natural compounds targeting the p53 pathway are of growing interest in neuroprotection as they may represent promising therapeutic approaches in the prevention of oxidative stress-dependent pathological processes underlying AD.

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Ser422 phosphorylation blocks human Tau cleavage by caspase-3: Biochemical implications to Alzheimer’s Disease

Cited by 17 publications

References 68 publications

Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

Tauopathy

The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease

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