Mechanisms of GNAO1-associated neurological disorders
Tremendous advances in the genetics of neurodevelopmental disorders have markedly improved the understanding of disease mechanisms. This project will focus on understanding the mechanisms of GNAO1 encephalopathies, a devastating but complex disorder, which exhibit multiple neurological symptoms. These include developmental delay and variable components of early onset epilepsy and/or hyperkinetic movement disorders (MDs). These symptoms are associated with mutations in the GNAO1 gene, which encodes the Gαo protein. GNAO1 mutation-associated neurological disorders include neurodevelopmental delay with involuntary movements (NEDIM, OMIM#617493) and early infantile epileptic encephalopathy (EIEE17, OMIM#615473). The number of identified patients and mutant alleles for EIEE17 or NEDIM is increasing rapidly. Gαo is the most abundant membrane protein in the mammalian central nervous system. It couples to multiple G protein-coupled receptors (GPCRs) including GABAB, α2 adrenergic, D2 dopamine, and adenosine A1 receptors; all are associated with both MDs and epilepsy. In addition, GPCRs are readily targetable by agonists and antagonists. This provides the possibility of treating GNAO1-associated neurological disorders. This project revealed a fundamental mechanistic distinction among these GNAO1 mutations: Loss-of-function (LOF) GNAO1 alleles are associated with epilepsy, while gain-of-function (GOF) GNAO1 alleles are associated primarily with MDs. However, this simple model is insufficient to explain all clinical observations. To explore this correlation, we have created mouse models carrying two of the most common human GNAO1 mutant alleles (G203R and R209H). They largely share the human pathophysiology; the G203R mouse model exhibits both MD and enhanced seizure propensity, while the R209H mutant results in MD alone, as seen in children with those mutations. Using these models, we can further explore mechanisms that lead to distinct patterns in human GNAO1 encephalopathies. To explore electrophysiological alterations in the Gnao1 G203R mutant mouse model, I performed patch clamp studies on cerebellar Purkinje cells. The results show a decreased frequency of both miniature inhibitory postsynaptic currents (mIPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs), suggesting a reduced presynaptic GABA release.This study provides a molecular and physiological understanding of different GNAO1 alleles in vitro, and identifies key candidate alleles for further analysis in in vivo mouse models and in human GNAO1-associated neurological disorders. Furthermore, our study may serve as a prototype for other correlations between reported monogenic mutations and human neurological disorders.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Feng, Huijie
- Thesis Advisors
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Neubig, Richard R.
- Committee Members
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Yuan, Yukun
Cox, Charles L.
Hegg, Colleen C.
Galligan, James J.
- Date
- 2019
- Subjects
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Nervous system
Diseases
Infantile spasms
Epilepsy
- Program of Study
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Pharmacology and Toxicology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- xxi, 295 pages
- ISBN
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9781085673228
1085673227
- Permalink
- https://doi.org/doi:10.25335/beab-rz56