“Does Dysfunctional BDNF Limit Remodeling the Aged Parkinsonian Striatum?”

MPF Award: “Does Dysfunctional BDNF Limit Remodeling the Aged Parkinsonian Striatum?”

Investigators: Kathy Steece-Collier, PhD and Natosha Mercado, BS

While there are a number of therapeutic options for individuals with Parkinson’s disease (PD), these therapies do not work uniformly well in all patients, and eventually many individuals with PD experience a lessening in the effectiveness of medications and significant side-effects like the abnormal involuntary movements known as dyskinesias develop. An interesting and underappreciated fact is that early-stage PD subjects receiving equivalent doses of Sinemet, the ‘gold standard’ PD drug, experience a magnitude of therapeutic response ranging from a 100% improvement to a 242% worsening. This variability in drug responsiveness of individuals with PD underscores the incredible diversity in clinical response in persons with this disease to standard-of-care anti-parkinsonian therapy, despite having similar degrees of disease pathology. Similar findings have been reported over the past several decades for the experimental “regenerative medicine” approach of transplanting new brain cells into PD patients; an approach that was once met with great enthusiasm and is regaining popularity worldwide. Indeed, while some PD patients have shown marked and lasting anti-parkinsonian benefit following transplanting of new nerve cells to replace those that die in the disease, many have also shown no or limited benefit. It was originally thought that the individuals that did not show therapeutic benefit must have “rejected” the newly transplanted brain cells. However, recently it came as a surprise to find that some of these individuals that came to autopsy numerous years after transplantation still had exceptionally large numbers of healthy appearing transplanted nerve cells!  So the question remains why do some individuals with healthy new brain cells not respond to these cells.

Our group recently discovered that a genetic variation that occurs in up to 40% (nearly half) of people in the general population, and in those with PD, impacts their responsiveness to anti-parkinsonian medication.  Specifically, PD individuals with this particular genetic variation, which is technically referred to as a “single nucleotide polymorphism” or SNP, diminishes the therapeutic effectiveness of Sinemet. The consequence of this particular SNP is that subjects with this genetic variation are unable to release an important “trophic” or supportive substance called BDNF (brain-derived neurotrophic factor) from their nerve cells. This deficit is thought to impair critical  communication between certain nerve cells, particularly those in brain regions effected by PD. Based on this biological effect, we hypothesize that this SNP is a genetic “risk factor” that underlies the impaired clinical response of some PD individuals to the brain repair strategy involving transplanting new dopamine producing brains cells.

To test the idea that PD patients with this genetic risk factor are the subpopulation of individuals that are resistant to the therapeutic benefit from transplantation, we have generated a genetic rat model of the human SNP.  We propose to use this novel experimental tool to characterize the effects of this genetic risk factor on the ability of newly grafted nerve cells to integrate with, and remodel/repair the brain of parkinsonian SNP rats.  IF we determine that this SNP is indeed a genetic risk factor predicting lack of responsiveness to reverse parkinsonism following transplantation of new brain cells, this would advance “personalized medicine” in the clinic by allowing physicians to advise genetic testing to screen PD patients for the most effective and lasting symptomatic therapy for each individual patient. If these studies funded by the MPF do determine that this SNP is a risk factor hindering brain repair, it may also serve to advance the field of regenerative medicine by allowing a better picture of the “real utility” of nerve cell transplantation. Specifically, if physicians could screen individuals likely not to respond favorably to this approach, it would better inform the PD community of the true promise of this experimental approach. Understanding whether this SNP does compromise brain repair also could provide rationale for development of ways to supplement the supportive compound BDNF in the brains of individuals with this SNP, potentially allowing for successful brain repair in all patients.