β-arrestin1 promotes tauopathy by transducing GPCR signaling, disrupting microtubules and autophagy

Woo, Jung-Aa; Yan, Yan; Kee, Teresa; Cazzaro, Sara; Percy, Kyle C McGill; Wang, Xinming; Liu, Tian; Liggett, Stephen B.; Kang, David E.

doi:10.26508/lsa.202101183

Cited by 11 publications

(9 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This data is in agreement with the inhibitory effect of β-arrestin1 on the formation of LC3 puncta and the reduction in p62-LC3 colocalization. These data are consistent with the observed role of β-arrestin1 in impeding p62/SQSTM1 flux and impairing destruction of misfolded tau ( 83 ) and underline the potential of β-arrestin proteins as drug targets for the therapy of neurodegenerative diseases. FTD includes a spectrum of clinical syndromes associated with various neurodegenerative diseases.…”

Section: The Role Of β-Arrestin Proteins In Cytoskeleton-associated N...supporting

confidence: 88%

“…β-arrestin2 protein and mRNA were significantly increased in the tau-FTD brain samples compared to the controls and in the brain samples of the P301S transgenic mice compared to the brains of the non-transgenic mice ( 85 ). A recent report has shown that β-arrestin1 levels are increased in the brains of FTD patients, and β-arrestins are essential for the β2 adrenergic receptor and mGluR2 glutamate receptor-mediated increase in pathogenic tau ( 83 ). Increased β-arrestin1 also causes the accumulation of pathogenic tau, whereas its reduction alleviates tau-induced pathology and rescues the impaired synaptic plasticity and cognitive abilities in PS19 mice.…”

Section: The Role Of β-Arrestin Proteins In Cytoskeleton-associated N...mentioning

confidence: 99%

See 1 more Smart Citation

Interactions between β-arrestin proteins and the cytoskeletal system, and their relevance to neurodegenerative disorders

Szénási

Turu²,

Hunyady³

2023

Front. Endocrinol.

View full text Add to dashboard Cite

β-arrestins, which have multiple cellular functions, were initially described as proteins that desensitize rhodopsin and other G protein-coupled receptors. The cytoskeletal system plays a role in various cellular processes, including intracellular transport, cell division, organization of organelles, and cell cycle. The interactome of β-arrestins includes the major proteins of the three main cytoskeletal systems: tubulins for microtubules, actins for the actin filaments, and vimentin for intermediate filaments. β-arrestins bind to microtubules and regulate their activity by recruiting signaling proteins and interacting with assembly proteins that regulate the actin cytoskeleton and the intermediate filaments. Altered regulation of the cytoskeletal system plays an essential role in the development of Alzheimer’s, Parkinson’s and other neurodegenerative diseases. Thus, β-arrestins, which interact with the cytoskeleton, were implicated in the pathogenesis progression of these diseases and are potential targets for the treatment of neurodegenerative disorders in the future.

show abstract

Section: The Role Of β-Arrestin Proteins In Cytoskeleton-associated N...supporting

confidence: 88%

Section: The Role Of β-Arrestin Proteins In Cytoskeleton-associated N...mentioning

confidence: 99%

Interactions between β-arrestin proteins and the cytoskeletal system, and their relevance to neurodegenerative disorders

Szénási

Turu²,

Hunyady³

2023

Front. Endocrinol.

View full text Add to dashboard Cite

show abstract

“…S3C ). To measure functional changes in synaptic plasticity imposed by the CHCHD2-T61I mutation, we carried out electrophysiological studies from ex vivo brain slices as we previously showed ( 35 ). Long-term potentiation (LTP) induced by theta-burst stimulation showed that 10-month-old CHCHD2-T61I Tg line U144 mice exhibit a significant reduction in hippocampal LTP compared with WT littermates ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Pathological characterization of a novel mouse model expressing the PD-linked CHCHD2-T61I mutation

Kee¹,

Wehinger²,

Gonzalez³

et al. 2022

Human Molecular Genetics

Self Cite

View full text Add to dashboard Cite

Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) is a mitochondrial protein that plays important roles in cristae structure, oxidative phosphorylation, and apoptosis. Multiple mutations in CHCHD2 have been associated with Lewy body disorders (LBDs), such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), with the CHCHD2-T61I mutation being the most widely studied. However, at present, only CHCHD2 knockout or CHCHD2/CHCHD10 double knockout mouse models have been investigated. They do not recapitulate the pathology seen in patients with CHCHD2 mutations. We generated the first transgenic mouse model expressing the human PD-linked CHCHD2-T61I mutation driven by the mPrP promoter. We show that CHCHD2-T61I Tg mice exhibit perinuclear mitochondrial aggregates, neuroinflammation, and have impaired long-term synaptic plasticity associated with synaptic dysfunction. Dopaminergic neurodegeneration, a hallmark of PD, is also observed along with α-synuclein pathology. Significant motor dysfunction is seen with no changes in learning and memory at one year of age. A minor proportion of the CHCHD2-T61I Tg mice (~10%) show a severe motor phenotype consistent with human Pisa Syndrome, an atypical PD phenotype. Unbiased proteomics analysis reveals surprising increases in many insoluble proteins predominantly originating from mitochondria and perturbing multiple canonical biological pathways as assessed by Ingenuity Pathway Analysis, including neurodegenerative disease-associated proteins such as tau, cofilin, SOD1, and DJ-1. Overall, CHCHD2-T61I Tg mice exhibit pathological and motor changes associated with LBDs, indicating that this model successfully captures phenotypes seen in human LBD patients with CHCHD2 mutations, and demonstrates changes in neurodegenerative disease-associated proteins, which delineates relevant pathological pathways for further investigation.

show abstract

“…We performed four different experimental assays [ 11 ] to determine the extent of β-arrestin binding. A proximity ligation assay [ 11 , 33 , 34 ] in transfected HEK-293 cells ( Figure 4 ) showed that C5-S and C6-S evoked β-arrestin binding to β 2 AR to approximately the same extent as the partial, balanced, β-agonist albuterol (ALB). In contrast, C-1S exhibited no β 2 AR: β-arrestin binding.…”

Section: Ascertainment Of Gs-biasing With Selected Compoundsmentioning

confidence: 99%

Biased β-Agonists Favoring Gs over β-Arrestin for Individualized Treatment of Obstructive Lung Disease

Токмакова

Kim

Goddard

et al. 2022

JPM

Self Cite

View full text Add to dashboard Cite

Signals from G-protein-coupled receptors (GPCRs) are the most frequently targeted pathways of currently prescribed therapeutics. Rather than being a simple switch, it is now evident that a given receptor can directly initiate multiple signals, and biasing to achieve signal selectivity based on agonist structure is possible. Biased agonists could direct therapeutically favorable pathways while avoiding counterproductive or adverse reaction pathways. For obstructive lung diseases, β2-adrenergic receptor (β2AR) agonists act at these receptors on airway smooth muscle (ASM) cells to open the airways by relaxing ASM, improving airflow and morbidity. However, these receptors signal to the G protein Gs (increasing cAMP and promoting relaxation), but also to β-arrestin (promoting desensitization and a loss of effectiveness). Indeed, β-agonist use is associated with adverse events in asthma pathogenesis and clinical outcomes which are related to desensitization. β-agonists favoring Gs coupling over β-arrestin binding would provide a means of tailoring bronchodilator therapy. In this review, we show how combinatorial methods with a 40 million compound agnostic library led to a new class of biased β-agonists that do not desensitize, providing an opportunity to personalize therapy in patients who experience poor efficacy or adverse effects from traditional balanced agonists.

show abstract

β-arrestin1 promotes tauopathy by transducing GPCR signaling, disrupting microtubules and autophagy

Cited by 11 publications

References 103 publications

Interactions between β-arrestin proteins and the cytoskeletal system, and their relevance to neurodegenerative disorders

Interactions between β-arrestin proteins and the cytoskeletal system, and their relevance to neurodegenerative disorders

Pathological characterization of a novel mouse model expressing the PD-linked CHCHD2-T61I mutation

Biased β-Agonists Favoring Gs over β-Arrestin for Individualized Treatment of Obstructive Lung Disease

Contact Info

Product

Resources

About