The etiology for the non-motor symptoms in PD, such as autonomic instability, sleep disturbance, and constipation, remain poorly understood. In their recent studies of PD neuropathology, Braaks and colleagues uncovered the dorsal motor nucleus of the vagus nerve (DMX) in the brain stem as the first region in the central nervous system to be affected by alpha-synuclein aggregation. Since DMX is an integral part of the autonomic nervous system, it is postulated that damage to this brain region may account for autonomic impairment in PD.
We propose to develop a transgenic pre-clinical model to selectively express mutant and wildtype alpha-synuclein in DMX. We will first confirm the progressive accumulation of alpha-synuclein aggregates in DMX. Furthermore, since vagal nerves from the DMX control gastrointestinal (GI) function, we will perform a variety of GI functional tests to examine whether alpha-synuclein pathology this brainstem nucleus is sufficient to elicit autonomic dysfunction reminiscent of that seen in PD patients.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Even though PD is usually characterized by prominent motor impairment, patients often suffer from non-motor symptoms such as autonomic dysfunction (i.e. GI and neurocardiological deficits). These deficits may occur prior to the onset of the classic motor symptoms and are often not responsive to the dopamine replacement therapy. Our study may provide evidence that alpha-synuclein toxicity in DMX as a key mechanism in the pathogenesis of autonomic dysfunction in PD, hence may offer a cellular target to alleviate aspects of non-motor symptoms in PD.
At the end of this experiment, we expect to confirm or refute the hypothesis that alpha-synuclein toxicity in DMX is responsible for aspects of autonomic dysfunction in PD transgenic mice. Moreover, our DMX-specific alpha-synuclein pre-clinical model may be useful to test novel therapeutics that could treat the autonomic dysfunction in PD.