The laboratory of Molecular Neuropsychiatry studies human psychiatric and neurological diseases using the method of cell biology, molecular biology, genetics, genomics, and animal models. Currently, we are focusing on Alzheimer's disease, autism, and schizophrenia.
In Alzheimer's disease, we have two primary focuses. We are interested in the biological functions of the Alzheimer amyloid protein precursor (APP). It has recently been shown that APP undergoes cleavage to release a cytoplasmic domain which can then translocate to the nucleus and apparently regulate transcription. This process, which is now thought to occur for several hundred proteins, is a novel form of signal transduction that has never before been fully appreciated. We are looking at this process to identify which genes are regulated by APP. We are also looking at similar processes with LDL-receptor related protein (LRP), another protein implicated in Alzheimer's disease.
Our second focus in Alzheimer's disease is characterizing the function of the protein calsenin, and related proteins, included the calsenin-like protein (CALP). Both of these proteins bind to the presinilins, which are involved in the cleavage of APP, noted above. These two proteins regulate that cleavage and modulate the accumulation of the amyloid Abeta protein, which is pathological in Alzheimer's disease. Interestingly, calsenin and CALP both also regulate the levels of potassium channels on the cell surface and play an important role in many processes involving cell-excitability. Calsenin can regulate long-term potentiation (LTP). We are currently exploring the role of calsenin in substance abuse and in Parkinson's disease, because of the role of this protein in nerve function. The related protein CALP is similarly being studied. It is also of note that calsenin appears to be critically involved in the sensing of pain.
In autism, we are using techniques of molecular genetics to identify, and ultimately characterize, genes that contribute to autism susceptibility. Using methods of linkage analysis followed by association, we have identified a region on chromosome 2 that appears to harbor an autism susceptibility gene. In that region, we have identified an aspartate-glutamate carrier (AGC1) that appears to contribute to autism susceptibility. We are characterizing AGC1 functionally using cell and animal models, while continuing to study it genetically. We are also working with a large consortium to identify additional autism susceptibility genes.
Finally, in schizophrenia, we are following up on microarray studies that implicate all the oligotendrocyte abnormalities in schizophrenia. Microarray studies carried out by the laboratory of Dr. Haroutunian and our laboratory, together with Dr. A. Fienberg, clearly demonstrated a reduction in schizophrenia of genes associated with oligotendrocytes. This finding has been replicated in multiple independent laboratories. Studies by Dr. P. Hof in the Department of Neuroscience have subsequently demonstrated a clear reduction in the number of oligotendrocytes in schizophrenia. These observations, coupled with more recent observations identifying neuregulin as a susceptibility gene for schizophrenia, have led us to postulate an oligotendrocytes etiology to schizophrenia. We are making use of cell biological and animal model to follow up on this initial observation.
Icahn School of Medicine
One Gustave L. Levy Place
New York, NY 10029