Objective/Rationale:
The use of antipsychotic drugs, all of which block dopamine D2 receptors, to treat schizophrenia and other psychotic states is associated with the development of motor acute, reversible adverse effects such as antipsychotic induced parkinsonism (AIP) which is clinically similar to PD, and chronic, late onset, tardive dyskinesia (TD), which is clinically similar to L-dopa induced dyskinesia (LID). Besides demographic and clinical risk factors, there is strong evidence for a genetic contribution to AIP or TD and several susceptibility genes have been reported. We suggest that these genes may also influence clinical features of PD.
Project description:
We will conduct a multi-facetted project to study the role of susceptibility genes for AIP and TD as possible risk modifying variants in PD for age of onset, disease severity, L-dopa treatment response and susceptibility to LID. DNA and clinical data have been collected from Jewish PD patients in Israel, and from Italian patients. In addition, we will use neuroimaging data from DAT-scans to evaluate the role of these genes in disease severity and progression. We will also study the effect of identified genetic variants on gene expression in blood cells and brain tissue.
Relevance to treatment of PD:
The identification of several AIP and TD-associated genes provides promising candidates for the study of potential PD modifying genes. Validation of AIP and TD associated genes as PD modifying genes will significantly advance the field by providing pharmacogenetic tools with clinical utility. Pharmacogenetic factors in susceptibility to LID are understudied. Identification of genetic risk factors for LID may assist in a priori identification of patients prone to develop this common and severe adverse effect and allow proper treatment planning.
Anticipated outcomes:
We hope to identify genes that influence cardinal feature of PD such as age of onset, severity, drug responsiveness and adverse effects (mainly LID) and will have utility in treatment planning. A comprehensive understanding of PD modifier genes and the functional role of the proteins they encode will expand our understanding of the disease at the neurobiological level and provide new targets for drug development.