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G?o is a major determinant of cAMP signaling in the pathophysiology of movement disorders.

ABSTRACT: The G protein alpha subunit o (G?o) 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 G?o is ill defined mechanistically. Here, we show that G?o dictates neuromodulatory responsiveness of striatal neurons and is required for movement control. Using in vivo optical sensors and enzymatic assays, we determine that G?o 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 G?o function in a neuron-type-specific fashion via a combination of a dominant-negative and loss-of-function mechanisms. Overall, our findings suggest that G?o and its pathological variants function in specific circuits to regulate neuromodulatory signals essential for executing motor programs.

SUBMITTER: Muntean BS

PROVIDER: S-EPMC7903328 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Muntean Brian S BS Masuho Ikuo I Dao Maria M Sutton Laurie P LP Zucca Stefano S Iwamoto Hideki H Patil Dipak N DN Wang Dandan D Birnbaumer Lutz L Blakely Randy D RD Grill Brock B Martemyanov Kirill A KA

Cell reports 20210201 5

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 inhib ...[more]

PMID: 33535037

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Project description:Movement disorders are a prominent and common feature in many autoantibody-associated neurological diseases, a group of potentially treatable conditions that can mimic infectious, metabolic or neurodegenerative disease. Certain movement disorders are likely to associate with certain autoantibodies; for example, the characteristic dyskinesias, chorea and dystonia associated with NMDAR antibodies, stiff person spectrum disorders with GAD, glycine receptor, amphiphysin or DPPX antibodies, specific paroxysmal dystonias with LGI1 antibodies, and cerebellar ataxia with various anti-neuronal antibodies. There are also less-recognized movement disorder presentations of antibody-related disease, and a considerable overlap between the clinical phenotypes and the associated antibody spectra. In this review, we first describe the antibodies associated with each syndrome, highlight distinctive clinical or radiological 'red flags', and suggest a syndromic approach based on the predominant movement disorder presentation, age, and associated features. We then examine the underlying immunopathophysiology, which may guide treatment decisions in these neuroimmunological disorders, and highlight the exceptional interface between neuronal antibodies and neurodegeneration, such as the tauopathy associated with IgLON5 antibodies. Moreover, we elaborate the emerging pathophysiological parallels between genetic movement disorders and immunological conditions, with proteins being either affected by mutations or targeted by autoantibodies. Hereditary hyperekplexia, for example, is caused by mutations of the alpha subunit of the glycine receptor leading to an infantile-onset disorder with exaggerated startle and stiffness, whereas antibodies targeting glycine receptors can induce acquired hyperekplexia. The spectrum of such immunological and genetic analogies also includes cerebellar ataxias and some encephalopathies. Lastly, we discuss how these pathophysiological considerations could reflect on possible future directions regarding antigen-specific immunotherapies or targeting the pathophysiological cascades downstream of the antibody effects.

Dataset Information

G?o is a major determinant of cAMP signaling in the pathophysiology of movement disorders.

Publications

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

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