Molecular genetic mechanisms of neuropsychiatric diseases and dementia
Mapping and Positional cloning of genes for human pathologies
Our research is focused on the identification of genes and cellular proteins that play a critical role in normal and pathological aspects of human behavior. To identify such genes and proteins we first use the strategies of linkage, genetic association analysis and positional cloning to isolate the mutant or polymorphic genes underlying the human diseases. We then develop functional assays to express these genes in vitro and in vivo to study their normal and pathogenic functions.
We are interested also in the study of evolutionary aspects of human populations, genome and specific genes in order to elucidate the phenomenon of some behavioral disorders prevalent in humankind.
Alzheimer's disease, schizophrenia and depression are three of the most common mental disorders and our primary interest.
The mutations in human presenilin 1 and presenilin 2 genes, which we and our colleagues described previously, are a major cause of familial early-onset Alzheimer's disease. The AD-mutations in the presenilins are supposed to enhance its proteolysis-associated activity, that in turn may result in elevated amyloid precursor protein cleavage and production of neurotoxic beta amyloid derivates. However, other "non-amyloid" mechanisms of pathogenic effects of presenilins have not yet been ruled out. The role of presenilins in most common "non-familial" AD cases, and cellular factors or chemical compounds which may modulate the activity of presenilins, are still unclear. Our studies search for factors that may regulate presenilin genes and interact with presenilin proteins. We search for population variations and modifications in promoters of presenilin 1 and presenilin 2 genes and measure the transcriptional activity of variable regulatory regions of presenilins. The potential exogenous and endogenous inhibitors or repressors of these elements are tested in neural human or rat cells. We also search for families of proteins that interact directly with presenilins or their targets (e.g., Amyloid Precursor Protein and Notch-receptors) and which may serve as modulators of presenilin mediated proteolysis. These studies will contribute to understanding of fundamental mechanisms of inter- and intra-cellular signaling and also provide potential targets for treatment of Alzheimer's disease neuro-degeneration.
More than 50% of AD have no association with mutations in encoding regions of presenilins and other known AD -genes (ApoE,APP). Thus, there must be other AD genes yet to be discovered. In order to identify such genes, we combine the methods of genetic association and linkage analysis in families and population groups of late-onset AD patients and age-matched non-demented individuals. We test the single nucleotide polymorphisms (SNPs) in several selected chromosomal loci to define the narrow genomic region and ultimately identify novel genes associated with AD.
Schizophrenia and Depression
The molecular-genetic mechanisms and genes for schizophrenia or affective disorders remains to be elusive. We are collecting large samples of schizophrenia and affective disorders from ethnically defined populations. The identification of specific SNPs haplotypes and linkage disequilibrium analysis for a few candidate loci and genes are currently of our particular interest. A MassARRAY MALDI system will be used for fine mapping of these loci. Recently two novel candidate-genes for schizophrenia have been isolated from two chromosomal loci by testing of multiple polymorphic markers in two population samples. These primary data are to be replicated in the genetic study of other population samples. To elucidate the biological significance of the candidate-genes found by genetic approach, the study of effects of up- and down regulation of the candidate- genes on neuroplasticity and neurotransmition signaling will be undertaken.
It is assumed that common diseases represent mainly polygenic or multifactorial diseases. The identification of the susceptible genes for such diseases is rather complicated. However, familial (Mendelian) transmission of diseases which may be clinically similar to common phenotypes is observed in rare families. We are interested in identifying and studying such families. Isolation of the disease genes in these rare families may help to elucidate the molecular mechanisms for more common forms of the human diseases.
We use unique resources in several genetic isolates and limited human populations. Large pedigrees of human families with autosomal-dominant and autosomal-recessive diseases with unknown gene defects are being collected . Currently, we apply strategies of positional cloning and direct screening of candidate-genes for variety of human diseases, including eg., morbid obesity with hyperphagia, a specific case of premature aging, eye-diseases, alopecia (baldness) and others.