Cdk5 increases MARK4 activity and augments pathological tau accumulation and toxicity through tau phosphorylation at Ser262

Saito, Taro; Oba, Toshiya; Shimizu, Sawako; Asada, Akiko; Iijima, Koichi; Ando, Kanae

doi:10.1093/hmg/ddz120

Cited by 30 publications

(26 citation statements)

References 53 publications

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“…Besides, hyperphosphorylated Tau protein has a double-helical structural change, which promotes the formation of NFTs and induces AD. Cyclin-dependent kinase 5 (CDK5) is a major regulatory enzyme for Tau phosphorylation, which can affect the phosphorylation of Tau (28). The inhibition of CDK5 can decrease the production of hyperphosphorylated Tau and thus decrease the damage to nerve cells.…”

Section: Discussionmentioning

confidence: 99%

Naringin ameliorates memory deficits and exerts neuroprotective effects in a mouse model of Alzheimer's disease by regulating multiple metabolic pathways

Meng

Wang

et al. 2021

Mol Med Rep

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The aim of the present study was to investigate the neuroprotective effects of naringin on the memory impairment of hydrocortisone mice, and to elucidate the potential underlying molecular mechanisms. In the present study, a hydrocortisone model was constructed. Novel object recognition, Morris water maze and step-down tests were performed in order to assess the learning and memory abilities of mice. Hematoxylin and eosin staining was used to observe pathological changes in the hippocampus and hypothalamus. Transmission electron microscopy was used to observe the ultrastructural changes in the hippocampus. Immunohistochemistry was used to detect the expression of ERα and ERβ. Western blotting was performed to detect the expression of each protein in the relevant system. It was found that naringin can significantly improve cognitive, learning and memory dysfunction in mice with hydrocortisone memory impairment. In addition, naringin can exert neuroprotective effects through a variety of mechanisms, including amyloid β metabolism, Tau protein hyperphosphorylation, acetylcholinergic system, glutamate receptor system, oxidative stress and cell apoptosis. Naringin can also affect the expression of phosphorylated-P38/P38, indicating that the neuroprotective effect of naringin may also involve the MAPK/P38 pathway. The results of the present study concluded that naringin can effectively improve the cognitive abilities of mice with memory impairment and exert neuroprotective effects. Thus, naringin may be a promising target drug candidate for the treatment of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Naringin ameliorates memory deficits and exerts neuroprotective effects in a mouse model of Alzheimer's disease by regulating multiple metabolic pathways

Meng

Wang

et al. 2021

Mol Med Rep

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“…Conversely, phosphorylation of p35 residues Ser59, Ser65, and Ser124 by protein kinase Cδ results in stabilization of p35 [50]. A recent study also showed CDK5 increases MARK4 activity through tau phosphorylation at Ser262 [51]. Lastly, prevention of protein phosphatase 1 and 2A activity by treatment of COS-7 cells with okadaic acid results in maintained phosphorylation of Thr138 and prevention of calpain-dependent cleavage of p35 into p25 [24].…”

Section: Regulation Of Cdk5 Activitymentioning

confidence: 97%

CDK5: Key Regulator of Apoptosis and Cell Survival

Roufayel

Murshid

2019

Biomedicines

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The atypical cyclin-dependent kinase 5 (CDK5) is considered as a neuron-specific kinase that plays important roles in many cellular functions including cell motility and survival. The activation of CDK5 is dependent on interaction with its activator p35, p39, or p25. These activators share a CDK5-binding domain and form a tertiary structure similar to that of cyclins. Upon activation, CDK5/p35 complexes localize primarily in the plasma membrane, cytosol, and perinuclear region. Although other CDKs are activated by cyclins, binding of cyclin D and E showed no effect on CDK5 activation. However, it has been shown that CDK5 can be activated by cyclin I, which results in anti-apoptotic functions due to the increased expression of Bcl-2 family proteins. Treatment with the CDK5 inhibitor roscovitine sensitizes cells to heat-induced apoptosis and its phosphorylation, which results in prevention of the apoptotic protein functions. Here, we highlight the regulatory mechanisms of CDK5 and its roles in cellular processes such as gene regulation, cell survival, and apoptosis.

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“…Neurodegeneration in the fly retina was analyzed as previously reported ( 48 ). Fly heads were fixed in Bouin’s fixative for 48 h at room temperature, incubated for 24 h in 50 m m Tris/150 m m NaCl, and embedded in paraffin.…”

Section: Methodsmentioning

confidence: 99%

“…qRT-PCR was carried out as previously reported ( 48 ). More than thirty flies for each genotype were collected and frozen.…”

Section: Methodsmentioning

confidence: 99%

Disulfide bond formation in microtubule-associated tau protein promotes tau accumulation and toxicity in vivo

Saito

Chiku

Oka

et al. 2021

Human Molecular Genetics

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Accumulation of microtubule-associated tau protein is thought to cause neuron loss in a group of neurodegenerative diseases called tauopathies. In diseased brains, tau molecules adopt pathological structures that propagate into insoluble forms with disease-specific patterns. Several types of posttranslational modifications in tau are known to modulate its aggregation propensity in vitro, but their influence on tau accumulation and toxicity at the whole-organism level has not been fully elucidated. Herein, we utilized a series of transgenic Drosophila models to compare systematically the toxicity induced by five tau constructs with mutations or deletions associated with aggregation, including substitutions at seven disease-associated phosphorylation sites (S7A and S7E), deletions of PHF6 and PHF6* sequences (ΔPHF6 and ΔPHF6*), and substitutions of cysteine residues in the microtubule binding repeats (C291/322A). We found that substitutions and deletions resulted in different patterns of neurodegeneration and accumulation, with C291/322A having a dramatic effect on both tau accumulation and neurodegeneration. These cysteines formed disulfide bonds in mouse primary cultured neurons and in the fly retina, and stabilized tau proteins. Additionally, they contributed to tau accumulation under oxidative stress. We also found that each of these cysteine residues contributes to the microtubule polymerization rate and microtubule levels at equilibrium, but none of them affected tau binding to polymerized microtubules. Since tau proteins expressed in the Drosophila retina are mostly present in the early stages of tau filaments self-assembly, our results suggest that disulfide bond formation by these cysteine residues could be attractive therapeutic targets.

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Cdk5 increases MARK4 activity and augments pathological tau accumulation and toxicity through tau phosphorylation at Ser262

Cited by 30 publications

References 53 publications

Naringin ameliorates memory deficits and exerts neuroprotective effects in a mouse model of Alzheimer's disease by regulating multiple metabolic pathways

Naringin ameliorates memory deficits and exerts neuroprotective effects in a mouse model of Alzheimer's disease by regulating multiple metabolic pathways

CDK5: Key Regulator of Apoptosis and Cell Survival

Disulfide bond formation in microtubule-associated tau protein promotes tau accumulation and toxicity in vivo

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