Aberrant Striatal Morphology: Impact on Therapeutic Efficacy in PD

While recent clinical trials of neural grafting for Parkinson’s disease (PD) are disappointing, rationale for "replacing" brain cells lost to disease remains strong. Many issues thought to underlie the overall lack of clinical success of grafting are under investigation. Primary among these is that despite the host (rat, pre-clinical model, human), survival of nerve cells, or neurons, grafted into the parkinsonian brain remains very low. While improving neuron survival is vital, other unknown factors may impose limitations. Specifically, we propose that even when science is able to successfully increase survival of grafted cells, even large numbers of cells may still be unable to produce optimal therapeutic benefit. Loss of the chemical dopamine, which occurs in PD, causes particular changes in form and structure of neurons in a brain region called ‘striatum’. We propose that these changes prevent grafted neurons from "hooking-up" with the patient’s own neurons in ‘normal’ways. Normal connections between neurons are critical for normal behavior. The mechanism by which dopamine loss induces structural change in neurons has been recently identified and allows scientists to prevent those changes in experimental animals (Day et al., 2006). Using this knowledge, we will examine whether preventing specific changes in neuron structure in parkinsonian rats, thereby leaving striatal neurons "normal" despite the loss of DA, will allow grafted cells to produce improved benefit. If preventing these changes allows grafted cells to establish normal connections, we believe that even a small graft will be better able to normalize motor behavior in individuals with PD.