Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

Larrivee, Casandra L.; Feng, Huijie; Quinn, Josiah A; Shaw, Vincent; Leipprandt, Jeffrey R.; Demireva, Elena Y.; Xie, Hua; Neubig, Richard R.

doi:10.1124/jpet.119.262733

Cited by 17 publications

(22 citation statements)

References 45 publications

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“…We wish to underline that the incompetence to interact with guanine nucleotides we ascribe to the Gln52 mutations in GNAO1 and GNAI1 is unlikely to be the general molecular feature for all the >30 point mutations identified in either gene in the pediatric encephalopathy patients. Indeed, we have explicitly shown that many encephalopathy mutants of Gαo are competent to uptake GTP in the BODIPY-GTPγS experiments ( [45] and our unpublished observations), just as it has been shown by others for the Gαo[Arg209His] mutant [46] or for Gαi1[Glu245Lys] (corresponding to Glu246 in Gαo, see Supplementary Figure S1) [47]. While the feature of differential effects of different encephalopathy mutations on the GTP binding and hydrolysis needs a dedicated and separate investigation, we conclude that some of the encephalopathy mutants, represented by the Gln52 mutations in Gαo and Gαi1 we described here, are deficient in these basic features of a G protein, and we further suggest that this basic biochemical deficiency and the devastating cellular outcomes of it are at the core of the dominant nature of these particular heterozygous mutations causing pediatric encephalopathy.…”

Section: Discussionsupporting

confidence: 76%

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

Solis

Кожанова

Koval

et al. 2021

Cells

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Heterotrimeric G proteins are immediate transducers of G protein-coupled receptors—the biggest receptor family in metazoans—and play innumerate functions in health and disease. A set of de novo point mutations in GNAO1 and GNAI1, the genes encoding the α-subunits (Gαo and Gαi1, respectively) of the heterotrimeric G proteins, have been described to cause pediatric encephalopathies represented by epileptic seizures, movement disorders, developmental delay, intellectual disability, and signs of neurodegeneration. Among such mutations, the Gln52Pro substitutions have been previously identified in GNAO1 and GNAI1. Here, we describe the case of an infant with another mutation in the same site, Gln52Arg. The patient manifested epileptic and movement disorders and a developmental delay, at the onset of 1.5 weeks after birth. We have analyzed biochemical and cellular properties of the three types of dominant pathogenic mutants in the Gln52 position described so far: Gαo[Gln52Pro], Gαi1[Gln52Pro], and the novel Gαo[Gln52Arg]. At the biochemical level, the three mutant proteins are deficient in binding and hydrolyzing GTP, which is the fundamental function of the healthy G proteins. At the cellular level, the mutants are defective in the interaction with partner proteins recognizing either the GDP-loaded or the GTP-loaded forms of Gαo. Further, of the two intracellular sites of Gαo localization, plasma membrane and Golgi, the former is strongly reduced for the mutant proteins. We conclude that the point mutations at Gln52 inactivate the Gαo and Gαi1 proteins leading to aberrant intracellular localization and partner protein interactions. These features likely lie at the core of the molecular etiology of pediatric encephalopathies associated with the codon 52 mutations in GNAO1/GNAI1.

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Section: Discussionsupporting

confidence: 76%

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

Solis

Кожанова

Koval

et al. 2021

Cells

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“…To date, 26 unique pathogenic variants in Gαo have been reported ( Kelly et al, 2019 ; Mihalek et al, 2017 ). Knockin mouse models carrying orthologous mutations to clinical variants in Gαo recapitulate movement dysregulation phenotypes ( Feng et al, 2019 ; Larrivee et al, 2019 ). Furthermore, pathogenic Gαo mutants show deficits in cAMP regulation in heterologous cellular assays ( Feng et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Gαo is a major determinant of cAMP signaling in the pathophysiology of movement disorders

et al. 2021

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SUMMARY The G protein alpha subunit o (Gαo) is one of the most abundant proteins in the nervous system, and pathogenic mutations in its gene ( GNAO1 ) cause movement disorder. However, the function of Gαo is ill defined mechanistically. Here, we show that Gαo dictates neuromodulatory responsiveness of striatal neurons and is required for movement control. Using in vivo optical sensors and enzymatic assays, we determine that Gαo provides a separate transduction channel that modulates coupling of both inhibitory and stimulatory dopamine receptors to the cyclic AMP (cAMP)-generating enzyme adenylyl cyclase. Through a combination of cell-based assays and rodent models, we demonstrate that GNAO1 -associated mutations alter Gαo function in a neuron-type-specific fashion via a combination of a dominant-negative and loss-of-function mechanisms. Overall, our findings suggest that Gαo and its pathological variants function in specific circuits to regulate neuromodulatory signals essential for executing motor programs.

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“…To seek understanding of the molecular etiology of GNAO1 encephalopathy, we rst probed the basic biochemical properties of the most frequent Gαo mutants: GTP uptake and hydrolysis, in comparison to the wild type protein. The GTP uptake analysis has so far been performed to three GNAO1 encephalopathy mutants: Q52P and Q52R displayed the complete loss of the GTP uptake 11 , while R209H was reported to display a faster GTP uptake 12 . We have applied the non-hydrolyzable uorescent BODIPY-GTPγS assay 8,[13][14][15][16][17] to monitor the GTP uptake properties of four Gαo variants: wild type, G203R, R209C, and E246K.…”

Section: Mutations In Gly203 Arg209 and Glu246 Results In Constitutive Gtp Binding Of Gαomentioning

confidence: 99%

“…R209H was reported to display a faster GTP uptake 12 . We have applied the non-hydrolyzable uorescent BODIPY-GTPγS assay 8,[13][14][15][16][17] to monitor the GTP uptake properties of four Gαo variants: wild type, G203R, R209C, and E246K.…”

mentioning

confidence: 99%

Restoration of the GTPase activity of Gαo mutants by Zn2+ in GNAO1 encephalopathy models

Larasati¹,

Savitsky²,

Koval³

et al. 2021

Preprint

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GNAO1 encephalopathy is a rare pediatric disease characterized by motor dysfunction, developmental delay, and epileptic seizures1-3. De novo point mutations in the gene encoding Gαo, the major neuronal G protein, lie at the core of this dominant genetic malady4. Half of the clinical case mutations fall on codons Gly203, Arg209, or Glu246 near the GTP binding/hydrolysis pocket of Gαo1-3. We here show that these pathologic mutations strongly speed up GTP uptake and inactivate GTP hydrolysis by Gαo, resulting in constitutive GTP binding by the G protein. Molecular dynamics simulations indicate that the mutations cause displacement of Gln205, the key to GTP hydrolysis. Decreased interactions with cellular partners including RGS19 suggest that despite the enhanced GTP residence, the mutants fail to fully adopt the activated conformation and thus transmit the signal. Through a high-throughput screening of approved drugs aiming at correction of this core biochemical dysfunction, we identify zinc pyrithione and Zn2+ ions as agents restoring the active conformation, GTPase activity, and cellular interactions of the encephalopathy mutants, with a negligible effect on wild type Gαo. We describe a Drosophila model of GNAO1 encephalopathy and show that dietary zinc supplementation restores the motor function and longevity of the mutant flies. With zinc supplements frequently recommended for diverse human neurological conditions, our work spanning from identification of the core biochemical defect in Gαo mutants and cellular interactions analysis to high-throughput screening and animal validation of the deficiency-correcting drug defines the potential therapy for GNAO1 encephalopathy patients.

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Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

Cited by 17 publications

References 45 publications

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

Gαo is a major determinant of cAMP signaling in the pathophysiology of movement disorders

Restoration of the GTPase activity of Gαo mutants by Zn2+ in GNAO1 encephalopathy models

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