GRK5 Deficiency Leads to Selective Basal Forebrain Cholinergic Neuronal Vulnerability

He, Minchao; Singh, Prabhakar; Cheng, Shaowu; Zhang, Qiang; Peng, Wei; Ding, Xuefeng; Li, Jun; Premont, Richard T.; Morgan, Dave; Burns, Jeffrey M.; Swerdlow, Russell H.; Suo, William Z.

doi:10.1038/srep26116

Cited by 13 publications

(14 citation statements)

References 55 publications

(82 reference statements)

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“…In line with these data, He at al. showed that GRK5 deficiency was also responsible for selective basal forebrain cholinergic neurodegeneration [ 79 ].…”

Section: Grk5 and Neurodegenerative Diseasesmentioning

confidence: 99%

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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“…In line with these data, He at al. showed that GRK5 deficiency was also responsible for selective basal forebrain cholinergic neurodegeneration [ 79 ].…”

Section: Grk5 and Neurodegenerative Diseasesmentioning

confidence: 99%

Targeting GRK5 for Treating Chronic Degenerative Diseases

Marzano

Rapacciuolo

Ferrara

et al. 2021

IJMS

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“…G protein-coupled receptor kinase-5 (GRK5) is one of the seven GRK family members whose primary function is to desensitize G protein-coupled receptors (GPCRs), which is essential for the desensitization and internalization of M2/M4 receptors [ 5 ]. Reduced levels of membrane (functional) GRK5 increased soluble β-amyloid in vitro , and decreased GRK5 membrane localization occurs in vivo as well as in an AD transgenic model and postmortem human AD brain samples [ 6 , 7 ]. GRK5 dysfunction mediates the deleterious cycle between cholinergic hypofunction and tau hyperphosphorylation, leading to increased β-amyloid deposition in the hippocampus [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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Our work explores the relationship between G protein-coupled receptor kinase-5 (GRK5) single nucleotide polymorphisms and Alzheimer's disease risk. We confirmed that GRK5 translocates from the cellular membrane to the cytosol in the hippocampus of Alzheimer's disease mice and that GRK5 deficiency promotes tau hyperphosphorylation, a hallmark of Alzheimer's disease pathology. Our results indicate that one functional variant, or mutant, of GRK5 (GRK5-Gln41Leu) decreased GRK5 translocation from the membrane to the cytoplasm and reduced tau hyperphosphorylation, whereas, another GRK5 mutant (GRK5-Arg304His) increased GRK5 translocation to the cytoplasm and promoted tau hyperphosphorylation. In addition, case-control studies revealed that GRK5-Gln41Leu is associated with a lower risk of late-onset Alzheimer's disease. Our findings suggest that the GRK5-Gln41Leu mutant may resist tau hyperphosphorylation by promoting GRK5 membrane stability and, in effect, may contribute to lower Alzheimer's disease risk.

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“…As aforementioned, the GRK5 deficiency also renders the mice more susceptible to Swedish APP-induced cognitive impairment [16]. In that study, the relevant mechanistic exploration revealed that the GRK5 deficiency causes selective cholinergic neuronal vulnerability and therefore renders the subjects more susceptible to damages induced by a variety of secondary insults, including excess Aß, free radicals, and others.…”

Section: Discussionmentioning

confidence: 88%

“…However, although it alone does not directly cause any impairment, it does worsen the damages induced or triggered by other insults. For example, in addition to the abovementioned study in which the homozygote GRK5KO worsened aging-induced cognitive impairment [18], we recently found that the heterozygote GRK5KO also worsened the cognitive impairment induced by over-expression of Swedish mutant APP in the GAP mice [16]. Therefore, although GRK5 deficiency alone does not directly cause detectable damage, it alters the subject's sensitivity and renders it more susceptible to the damages induced or triggered by other insults.…”

Section: Discussionmentioning

confidence: 96%

“…Compelling evidence suggests that profound basal forebrain cholinergic (BFC) neurodegeneration is associated with cognitive impairment in AD and other neurodegenerative disorders associated with memory dysfunction, such as Lewy body dementia (LBD) [12-15]. We recently found that G protein-coupled receptor kinase-5 (GRK5) deficiency leads to selective basal forebrain cholinergic (BFC) neuronal vulnerability, which renders the subjects more susceptible to cognitive impairment induced by Swedish mutant ß-amyloid precursor protein (APP) [16]. This finding has let us to speculate whether the same mechanism may also mediate OSA-triggered cognitive impairment.…”

Section: Introductionmentioning

confidence: 99%

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GRK5 deficiency leads to susceptibility to intermittent hypoxia-induced cognitive impairment

Singh

Peng

Zhang

et al. 2016

Behavioural Brain Research

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Obstructive sleep apnea (OSA) leads to cognitive impairment in about 25% patients, though it remains elusive what makes one more susceptible than the other to be cognitively impaired. G protein-coupled receptor kinase-5 (GRK5) deficiency is recently found to render subjects more susceptible to cognitive impairment triggered by over-expression of Swedish mutant ß-amyloid precursor protein. This study is to determine whether GRK5 deficiency also renders subjects more susceptible to the OSA-triggered cognitive impairment. Both wild type (WT) and GRK5 knockout (KO) mice were placed in conditions absence and presence of intermittent hypoxia (IH) with 8%/21% O2 90-second cycle for 8 hours a day for a month, and then followed by behavioral assessments with battery of tasks. We found that the selected IH condition only induced marginally abnormal behavior (slightly elevated anxiety with most others unchanged) in the WT mice but it caused significantly more behavioral deficits in the KO mice, ranging from elevated anxiety, impaired balancing coordination, and impaired short-term spatial memory. These results suggest that GRK5 deficiency indeed makes the mice more susceptible to wide range of behavioral impairments, including cognitive impairments.

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GRK5 Deficiency Leads to Selective Basal Forebrain Cholinergic Neuronal Vulnerability

Cited by 13 publications

References 55 publications

Targeting GRK5 for Treating Chronic Degenerative Diseases

Targeting GRK5 for Treating Chronic Degenerative Diseases

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

GRK5 deficiency leads to susceptibility to intermittent hypoxia-induced cognitive impairment

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