ABSTRACT: Evaluation of the Striatum-enriched Genes CalDAG-GEF1 and CalDAG-GEF2 as Targets for the Treatment and Prevention of L-DOPA Induced Dyskinesia
The most widely prescribed therapy for Parkinson’s disease is levodopa (L-DOPA), which allows patients to regain motor control. However, many patients develop adverse reactions to L-DOPA, including abnormal involuntary movements termed dyskinesias. We seek to understand the basis of these abnormal movements by studying genes that we discovered in animal models of dyskinesias. We will test whether manipulation of these genes can alleviate L-DOPA-induced abnormal movements in animals, thereby laying the groundwork for novel therapeutic targets.
Two of the genes that we discovered to be abnormally regulated in animal models of dyskinesia, called CalDAG-GEF1 and CalDAG-GEF2, are well situated to play a central role in driving L-DOPA-induced movements. These genes are expressed in the striatum, which is the main dopamine-modulated, motor-control center of the brain that suffers loss of dopamine in Parkinson’s disease. These genes can activate ERK proteins, which mediate abnormal motor responses to L-DOPA. We will test whether manipulation of the CalDAG-GEFs can alleviate L-DOPA-induced dyskinesias by using two strategies: First, we will test whether mice that we have engineered to lack CalDAG-GEF1 or 2 are resistant to developing L-DOPA-induced motor complications. Second, we will use viruses to either repress or activate the CalDAG-GEFs in parkinsonian rodents, to test for mitigation of motoric side-effects at various stages of L-DOPA therapy.
The most widely prescribed therapy for Parkinson’s disease is levodopa (L-DOPA), which allows patients to regain motor control. However, many patients develop adverse reactions to L-DOPA, including abnormal involuntary movements termed dyskinesias. We seek to understand the basis of these abnormal movements by studying genes that we discovered in animal models of dyskinesias. We will test whether manipulation of these genes can alleviate L-DOPA-induced abnormal movements in animals, thereby laying the groundwork for novel therapeutic targets.
Two of the genes that we discovered to be abnormally regulated in animal models of dyskinesia, called CalDAG-GEF1 and CalDAG-GEF2, are well situated to play a central role in driving L-DOPA-induced movements. These genes are expressed in the striatum, which is the main dopamine-modulated, motor-control center of the brain that suffers loss of dopamine in Parkinson’s disease. These genes can activate ERK proteins, which mediate abnormal motor responses to L-DOPA. We will test whether manipulation of the CalDAG-GEFs can alleviate L-DOPA-induced dyskinesias by using two strategies: First, we will test whether mice that we have engineered to lack CalDAG-GEF1 or 2 are resistant to developing L-DOPA-induced motor complications. Second, we will use viruses to either repress or activate the CalDAG-GEFs in parkinsonian rodents, to test for mitigation of motoric side-effects at various stages of L-DOPA therapy.
Co-author: Jill Crittenden