The influence of two functional genetic variants of GRK5 on tau phosphorylation and their association with Alzheimer's disease risk

Zhang, Yuan; Zhao, Jianghao; Yin, Mingkang; Cai, Yujie; Liu, Shengyuan; Wang, Yan; Zhang, Xingliang; Cao, Hao; Chen, Ting; Huang, Pengru; Mai, Hui; Liu, Zhou; Tao, Hua; Zhao, Bin; Cui, Lili

doi:10.18632/oncotarget.20283

Cited by 15 publications

(16 citation statements)

References 41 publications

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“…Subsequently, Zhao et al confirmed these results and also demonstrated that in the hippocampus of global GRK5-KO mice, the activity of both tau and GSK3β resulted increased and correlated with AD phenotype [ 81 ]. Finally, Zhang et al demonstrated that in aged amyloid precursor protein ( APP ) and presenilin 1 ( PSEN1 ) double transgenic mice (APP +/− /PS1 +/− ), the reduced levels of GRK5 on plasma membrane correlated with the onset of AD [ 82 ].…”

Section: Grk5 and Neurodegenerative Diseasesmentioning

confidence: 99%

“…The importance of GRK5 in the pathogenesis of AD has also been suggested by studies in humans. In particular, genetic sequencing has identified two functional SNPs in the grk5 gene, rs2230345 (GRK5-Q41L) and rs2230349 (GRK5-arginine [R] 304 histidine [H]) that have been linked to AD risk [ 82 ]. Specifically, Zhang et al demonstrated in mice that the functional variant Q41L impaired the ability of GRK5 to translocate from the membrane to the cytoplasm and was associated with decreased levels of phosphorylated tau.…”

Section: Grk5 and Neurodegenerative Diseasesmentioning

confidence: 99%

“…Conversely, these authors demonstrated that the R304H variant enhanced the ability of GRK5 to translocate to the cytoplasm and to promote tau hyperphosphorylation. Additionally, in case-control studies in humans, they revealed that the Q41L variant is associated with a lower risk of late-onset AD [ 82 ]. Although the data described above suggest that GRK5 depletion contributes to neurodegeneration, Arawaka and colleagues have reported that high levels of GRK5 (both mRNA and protein) are accumulated in the brains of patients with Parkinson’s disease (PD) [ 83 , 84 ].…”

Section: Grk5 and Neurodegenerative Diseasesmentioning

confidence: 99%

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Targeting GRK5 for Treating Chronic Degenerative Diseases

Marzano

Rapacciuolo

Ferrara

et al. 2021

IJMS

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G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors and they are responsible for the transduction of extracellular signals, regulating almost all aspects of mammalian physiology. These receptors are specifically regulated by a family of serine/threonine kinases, called GPCR kinases (GRKs). Given the biological role of GPCRs, it is not surprising that GRKs are also involved in several pathophysiological processes. Particular importance is emerging for GRK5, which is a multifunctional protein, expressed in different cell types, and it has been found located in single or multiple subcellular compartments. For instance, when anchored to the plasma membrane, GRK5 exerts its canonical function, regulating GPCRs. However, under certain conditions (e.g., pro-hypertrophic stimuli), GRK5 translocates to the nucleus of cells where it can interact with non-GPCR-related proteins as well as DNA itself to promote “non-canonical” signaling, including gene transcription. Importantly, due to these actions, several studies have demonstrated that GRK5 has a pivotal role in the pathogenesis of chronic-degenerative disorders. This is true in the cardiac cells, tumor cells, and neurons. For this reason, in this review article, we will inform the readers of the most recent evidence that supports the importance of targeting GRK5 to prevent the development or progression of cancer, cardiovascular, and neurological diseases.

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Section: Grk5 and Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Grk5 and Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Grk5 and Neurodegenerative Diseasesmentioning

confidence: 99%

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Targeting GRK5 for Treating Chronic Degenerative Diseases

Marzano

Rapacciuolo

Ferrara

et al. 2021

IJMS

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“…Increased calcium concentration could activate Gq/G11 proteins/phospholipase C (PLC) pathway [ 22 ] which, in turn, could modify tau, making it more toxic. Both excessive calcium level and increased tau toxicity lead to neuronal death [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Dangerous Liaisons: Tau Interaction with Muscarinic Receptors

Wysocka

Pałasz

Steczkowska

et al. 2020

CAR

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: The molecular processes underlying neurodegenerative diseases (such as Alzheimer's Disease - AD) remain poorly understood. There is also an imperative need for disease-modifying therapies in AD since the present treatments, acetylcholinesterase inhibitors and NMDA antagonists, do not halt its progression. AD and other dementias present unique pathological features such as that of microtubule associated protein tau metabolic regulation. Tau has numerous binding partners, including signaling molecules, cytoskeletal elements and lipids, which suggests that it is a multifunctional protein. AD has also been associated with severe loss of cholinergic markers in the brain and such loss may be due to the toxic interaction of tau with cholinergic muscarinic receptors. By using specific antagonists of muscarinic receptors it was found in vitro that extracellular tau binds to M1 and M3 receptors and which the increase of intracellular calcium found in neuronal cells upon tau-binding. However, so far, the significance of tau signaling through muscarinic receptor in vivo in tauopathic models remains uncertain. The data reviewed in the present paper highlight the significant effect of M1 receptor/tau interaction in exacerbating tauopathy related pathological features and suggest that selective M1 agonists may serve as a prototype for future therapeutic development toward modification of currently intractable neurodegenerative diseases, such as tauopathies.

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“…Tau is a very soluble hydrophilic protein [29]. Full-length tau remains soluble in solution up to 10M before it can aggregate.…”

Section: The Tau Pathology Catalystmentioning

confidence: 99%

Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

et al. 2017

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Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration.

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The influence of two functional genetic variants of GRK5 on tau phosphorylation and their association with Alzheimer's disease risk

Cited by 15 publications

References 41 publications

Targeting GRK5 for Treating Chronic Degenerative Diseases

Targeting GRK5 for Treating Chronic Degenerative Diseases

Dangerous Liaisons: Tau Interaction with Muscarinic Receptors

Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

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