This grant builds upon the research from a prior grant: Generation of a dorsal motor nucleus X (DMX) specific pre-clinical model of alpha synuclein overexpression to study the etiology of autonomic dysfunction in PD
Promising Outcomes of Original Grant:
According to Braak Staging of PD Pathology, the dorsal motor nucleus (DMN) is one of the earliest brain nuclei that accumulate alpha-Synuclein (aSyn) pathology, but the pathogenic significance of this finding remains unclear. Our original funded grant allowed us to develop a novel PD pre-clinical model that selectively expresses mutant aSyn-A53T in the DMN. This model is valuable to test the hypothesis that aSyn expression in DMX is sufficient to trigger autonomic (e.g. cardiac and gastrointestinal) deficits mimicking PD.
Objectives for Supplemental Investigation:
In the study supported by this MJFF supplement, we will first complete gastrointestinal and cardiovascular functional studies of the novel DMN-specific alpha-synuclein pre-clinical. These studies will help us to address our original hypothesis whether the expression of mutant aSyn in the DMN is sufficient to elicit non-motor dysfunction reminiscent of that seen in PD patients. As a new direction in this supplement that is based on the valuable PD pre-clinical resources we have developed thus far, we will test another critical prediction of Braak hypothesis - that seeding aSyn aggregation in DMN may trigger the spreading of aSyn aggregation to other brain regions critically relevant to PD, including the pons and midbrain.
Importance of This Research for the Development of a New PD Therapy:
Our study will use a novel series of PD pre-clinical models to test two critical hypotheses proposed by Braak and colleagues based on their extensive study of PD pathology: 1) that aSyn accumulation in DMN is sufficient to cause autonomic symptoms mimicking those in PD and 2) that aSyn accumulation in DMN may trigger aSyn pathology in other brain regions (e.g. midbrain). Our study may help to define the critical roles of aSyn in DMN in the onset and progression of PD, and hence may provide novel mechanistic clues and valuable pre-clinical models to develop novel therapy for PD.
Final Outcome
We have successfully developed a novel genetically-engineered transgenic pre-clinical model expressing a disease-causing form of human alpha Synuclein (aSyn) in the Dorsal Motor Nucleus, a brain region accumulating aSyn protein at an early stage of Parkinson’s disease (PD). Our results show that the transgenic models but not control littermates have impaired autonomic regulation of heart rate, a disease symptom mimicking the autonomic dysfunction in PD. Moreover, our study also shows that the accumulation of aSyn protein at the dorsal motor nucleus, which is also similar to that in the patients. Thus, our study suggests that aSyn toxicity in the dorsal motor nucleus may play a causal role in eliciting aspects of autonomic dysfunction in PD.