The goals of the Mabb lab are to provide a more unified understanding as to how pervasive neurological disorders in the ubiquitin pathway can lead to distinct and overlapping phenotypes. We seek to gain a basic understanding of E3 pathways in the nervous system, which may ultimately allow for the design of therapeutic intervention strategies for various rare, yet devastating, neurological disorders.
How do human-associated mutations and disruptions in E3 ubiquitin ligases alter neuronal substrates and properties in distinct neuronal types?
We focus on E3 disease-associated mutations in neurological disorders to understand how they impact substrate ubiquitination and neuronal properties, such as changes in synaptic transmission and neuronal morphology in different neuron types. As a first pass, we utilize dissociated cortical neuron cultures, which express both excitatory and inhibitory neurons and allow one to assess the impacts on both cell types in vitro. Using this model system, we are also employing CRISPR technologies to disrupt E3 ligases involved in neurological disease.
How do human-associated mutations and disruptions in E3 ubiquitin ligases alter neural behaviors and hormonal signaling pathways?
For reported E3 mutations that are associated with disease, very few animal models have been created to recapitulate these rare disorders. We are interested in Gordon-Holmes syndrome, in which no therapy currently exists. Gordon-Holmes syndrome is characterized by ataxia, cerebellar atrophy, and hypogonadotropic hypogonadism. Individuals have disrupted hormone signaling in response to gonadotropin-releasing hormone (GnRH). Intriguingly, Triad3/RNF216 mutations have been identified in patients with Gordon-Holmes syndrome. These individuals exhibit disruptions in the pituitary axis, cerebellar atrophy, and dementia, strongly indicating that hormonal signaling and the mechanisms mediating cognition are perturbed. Even more compelling, the Triad3 substrate Arc (an immediate early gene) is disrupted in neurodegerative disorders and would serve as a suitable readout for neurodegeneration in Gordon-Holmes. To delineate the mechanisms of Triad3 function in specific brain regions, we are using a conditional KO mouse targeting Triad3 to examine its biological relevance in cerebellar and hippocampal neurodegeneration and signaling in the hypothalamus and pituitary in vivo. The generation of these mouse models will allow us to assess hormonal, behavioral, and physiological phenotypes that may underlie that of Gordon-Holmes syndrome.
What are the substrates for E3 ubiquitin ligases that are disrupted in neurological disorders?
It is estimated that there are 500 - 1,000 human ubiquitin E3s, some of which are disrupted in human neurological disorders. We are interested in developing novel approaches for the identification of E3 ubiquitin ligase substates in the brain. We have developed a method which allows for brain-specific detection of substrates for any E3 ubiquitin ligase. Using our assay, we would like to embark on a journey to characterize the "neuronal ubiquitome".
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