Molecular Mechanisms regulating neurodengeration & 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 ongoing research on neurodegeneration and neurodevelopmental disorders is described below.
Neurodegenerative disorders
Neurodegenerative diseases such as AD, PD and 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), these do not slow down the relentless loss of neurons and therefore the disease progresses. Our lab is interested in identifying molecules that play a key role in either promoting or preventing neurodegeneration 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. We recently discovered that activation of one of the members of this family of proteins, HDAC3, plays a central role in promoting neurodegeneration. In ongoing studies funded by the NIH, we are investigating the role of HDAC3 in the pathogenesis of Huntington’s disease.
Another protein of interest to the lab is FoxG1, a transcription factor 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 are currently generating 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.
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. 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. While reduced MeCP2 activity causes Rett syndrome, elevated activity of this protein as a result of duplication or triplication of the MeCP2 gene causes a 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, these mice display neurological deficiencies and die early in adulthood. We find that MeCP2 transgenic mice display neuronal loss in certain brain regions 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 that 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, which is characterized by spasticity, mental retardation, and seizures. We are exploring whether MeCP2 duplication syndrome and Alexander disease share mechanistic commonalities.
