How could pre-clinical research models be used to study DNRS with relevance to humans?

Dr. Gary Miller and Dr. Todd Sherer discuss Dr. Miller's new VMAT2-deficient mouse model, published in the Journal of Neuroscience.

TS: What features of your model represent the clearest advance over existing models?

GM: The VMAT2LO mice display multiple non-motor symptoms of PD and these symptoms appear to be due to the widespread monoaminergic dysfunction that is also seen in PD. Further, the mice display tyrosine hydroxylase-positive neuron loss, elevated alpha-synuclein levels, and L-DOPA responsive motor deficits.

TS: Which features best mimic PD?

GM: For the non-motor symptoms, the dramatic loss in olfactory function and the onset of depressive symptoms stand out.  We also think that the deficits in norepinephrine and serotonin, in addition to those in the dopamine system more accurately reflect the widespread monoaminergic dysfunction that occurs in PD.

TS: What aspects of human PD are missing or have yet to be studied in your model?

GM: We have yet to study altered cardiovascular function in the mice.  There is evidence of autonomic dysfunction in PD, and given the prominent role of catecholamines in cardiovascular regulation, we suspect that they will have some problems.  We hope to perform these studies soon. We would also like to evaluate executive function, but such studies are virtually impossible in mice. Mice just can’t perform some of the critical tasks necessary to assess this.

TS: Are there unusual features present in your model that are not PD related?

GM: To this point we really haven’t seen any features that one wouldn’t consider to be PD related.  However, it is important to note that these animals have an immediate reduction of dopamine, norepinephrine, and serotonin.  For example, at 2 months of age, they have a loss of dopamine (80% loss) similar to that of an advance PD patient, but appear to be normal.  It is not until they lose a substantial portion of their already low dopamine levels that they exhibit the motor symptoms.  So they start low, but the symptoms appear to progress in a manner that parallels monoamine loss and degeneration.

TS: Your comprehensive characterization of the model included assessment of vision, muscle strength and sensory function. Why is this important for interpreting the behavioral phenotype of the model?

GM: Since the mice expressed so many behavioral deficits, we were concerned that they were just impaired in every way.  We first needed to know that they mice had the capacity to perform certain tests (e.g. if they can’t see, they can’t navigate a maze).  We then consulted with movement disorder specialists to determine which functions are generally intact in PD patients.  They suggested that vision, muscle strength, and sensory function would be expected to be within normal limits in the PD population. By confirming that functions that are typically normal in PD patients were also normal in the mice support the idea that the observed non-motor symptoms were specific to the monoaminergic dysfunction.

Based on our previous work, we have seen that many of the toxicant-based models (MPTP, paraquat, rotenone) result in the animals being sick and lethargic, which makes it difficult to discern if their behavior is PD related or due to the systemic toxicity.  By demonstrating that many physiological functions are normal we are confident that the deficits are due to the monoaminergic dysfunction.

TS: How will the model be best used to study PD?

GM: We think that this progressive model will be a great way to study compounds aimed at slowing disease progression.  Since we have a battery of non-invasive behavioral tests, we can monitor the time of onset of these symptoms.  For example, we see olfactory loss at 4 months, depressive symptoms after 12 months, and loss of TH neurons around 18 months.  While it will take a while to get the results, we can see how long-term therapies can help prevent the development of the various symptoms.

Also, if one wanted to test different antidepressants to treat PD, these mice, which display depressive features in the presence of PD related nigrostriatal dysfunction, could be very useful.

TS: Is the model available to the broader research community?

GM: We are happy to share the mice with the research community.  There are material transfer agreements that need to be place prior to distribution.

Taylor TN, Caudle WM, Shepherd KR, Noorian A, Jackson, CR, Iuvone PM, Weinshenker D, Greene JG, Miller GW. Nonmotor symptoms of Parkinson's Disease Revealed in an Animal Model with Reduced Monoamine Storage Capacity. Journal of Neuroscience. Jun 24 2009.