Molecular mechanisms regulating neurodegeneration & brain development
Research in the lab is centered on understanding the molecular mechanisms regulating neurodegeneration. Specifically, primary cultures of neurons, transgenic and knockout mice, and animal models of neurological disease are used to study genes, proteins, and signal transduction pathways regulating neuronal cell death. We are also interested in identifying chemical compounds that protect the brain from neurodegeneration. The long-term objective of the laboratory’s research is to develop strategies to prevent, treat, or cure degenerative diseases of the brain. Recently, we have expanded our interests to investigate neurodevelopmental disorders also. Our research has been funded by grants from the National Institutes of Health (NIH), Department of Defense, the National Science Foundation and private foundations. Our ongoing research on neurodegeneration and neurodevelopmental disorders is described below.
Neurodegenerative disorders
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease (HD) are progressive and fatal disorders affect millions of individuals in the U.S. alone costing the economy over $100 billion annually. While there are drugs that can reduce the symptoms associated with some of these diseases (for example, Parkinson’s disease), they do not slow down the relentless loss of neurons and therefore the disease progresses. Our lab is interested in identifying molecules that regulate the survival or death of neurons and whose altered function contributes to neurodegenerative disorders. Once identified, such molecules can then be targeted in the development of effective therapeutic strategies for these disorders. Much of our focus has been on histone deacetylases (HDACs) a family of 18 proteins initially identified based on their ability to repress gene expression through the deacetylation of histones, but which are now known to have a variety of other functions mediated through the deacetylation of non-histone proteins residing in the nucleus, cytoplasm or mitochondria. In studies supported by the NIH, we discovered that activation of one of the members of this family of proteins, HDAC3, plays a central role in promoting neurodegeneration. We are studying the mechanism by which HDAC3 promotes neurodegeneration.
The lab is also interested in FoxG1, a protein belonging to the Forkhead family of transcription factors that is critical for proper brain development where it controls the production of neurons by regulating proliferation of neural progenitor cells. Mice that lack FoxG1 have a severely underdeveloped brain and die early during gestation. But FoxG1 is highly expressed in the adult brain where its function had not been studied. We recently found that FoxG1 maintains the survival of mature neurons. We have been investigating the molecular mechanism through which the activity of FoxG1 is regulated and the mechanism by which FoxG1 affects other molecules to maintain the survival of neurons. As part of an NIH-funded project, we generated transgenic mice that express elevated levels of FoxG1. These mice will be used to test whether elevated FoxG1 can protect mice against neurodegenerative diseases such as Huntington’s disease. Another Forkhead protein of interest to the lab is FoxP1. FoxP1 is expressed selectively in the striatum and cortex, two regions of the brain that are selectively degenerate in HD. In studies funded by the NIH we found that FoxP1 expression is reduced in the striatum of HD patients and in HD mouse models. This reduction likely contributes the the loss of neurons in HD. In humans, FoxP1 mutations cause mental retardation and other cognitive deficits.
In addition to understanding the molecular biology of neurodegeneration the lab has been identifying chemical compounds that protect neurons from death. This drug discovery effort has led to the identification of several indolone and benzoxazine compounds that are highly protective in cell culture models and animal models of neurodegenerative diseases. Exactly how these neuroprotective compounds act is an area of interest.
Neurodevelopmental disorders
We have recently become interested in MeCP2, a gene that can repress gene transcription globally as well as locally. Loss-of-function mutations in the MeCP2 gene cause Rett syndrome, a neurodevelopmental disorder characterized by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability. On the other hand, elevated activity of MeCP2 as a result of gene duplication or triplication causes another neurological disorder called MeCP2 duplication syndrome. Patients with this disorder are born normal but then display progressive mental retardation, spasticity, epilepsy, and die at adulthood. We are studying MeCP2 duplication syndrome using transgenic mice that make 3-4 times more MeCP2 than normal. Like patients with MeCP2 duplication syndrome, these mice display neurological deficits and die early in adulthood. The mice display neuronal loss in certain brain regions coincident with the neurological symptoms and just before they die. We are characterizing other abnormalities in the MeCP2 transgenic brain with the goal of getting a better understanding of why human patients with MeCP2 duplication syndrome suffer the neurological phenotype that they do. A recent discovery we have made is that astrocytes within certain brain regions of the MeCP2 transgenic mice have high levels of a protein called GFAP. Interestingly, increased GFAP production is the primary cause of another neurological brain disorder called Alexander disease, characterized by spasticity, mental retardation, and seizures. These symptoms are also observed in many patients with MeCP2 duplication syndrome. We are exploring whether MeCP2 duplication syndrome and Alexander disease share mechanistic commonalities.
While abnormal function of HDAC3 contributes to neurodegeneration, recent research in the lab on brain-specific conditional knockout mice has revealed that HDAC3 plays an essential role in brain development. Neuronal migration and formation of proper lamination in the cortex is disrupted in mice lacking HDAC3 in the brain. Exactly how HDAC3 regulates proper brain development is being studied.
