Maladaptive Nigrovagal Pathophysiology in Parkinsonism

Recent studies have shown that Parkinson's disease (PD), the second most common neurodegenerative disorder in America, has non-motor features such as gastric dysmotility, sleep dysfunction, and constipation. It has also become apparent from patient studies that such symptoms very frequently present in patients many decades prior to the diagnosis of PD. Studies suggest that a combination of insults to the lining of the stomach and intestines causes the accumulation of a misfolded protein called alpha synuclein. Examples of insults that can cause accumulation of alpha synuclein include exposure to pesticides and insecticides in combination with certain food substances that are rich in a substance called lectin. Examples of pesticides that may play a role include paraquat and rotenone. These toxic chemicals may gain entry into the stomach and intestine when raw or uncooked contaminated foods are consumed. Many common foods such as eggs, vegetables, and fruits are rich in lectins when consumed without cooking. Our recent published studies indicate that rats fed with paraquat at very low levels, in combination with lectins, can cause PD-like symptoms that respond to levodopa, the commonly used medication used to treat PD. Detailed examination of their nervous system and the brain indicate that the harmful protein alpha synuclein is transported from the gut via the vagus nerve to the brain and then into an area called the substantia nigra in the deep portion of the brain. Damage to the cells in the substantia nigra causes the classic symptoms of PD. Evaluation of the nerve cells of the vagus nerve that reside in the brainstem indicates that they are overactive in a futile attempt to speed up the contractions of the stomach and the intestine to reduce mobility of the gut. This hyperactivity of the nerve cells of the vagus appears to be driven by the substantia nigra. This combination of increased activity in the nervous control of the gut in response to the accumulation of alpha synuclein appears to cause further damage to the brain and is termed 'maladaptive plasticity,' as it appears to further accelerate the progression of motor and non-motor symptoms of PD.

Therefore, the rationale for our study is to evaluate this maladaptive plasticity and find ways to limit the damage caused by it so that we can arrest the progression of disease or even find ways to prevent PD and, in particular, early non-motor findings such as constipation and sleep disturbances. Using a variety of newly described techniques that allow us to evaluate brain structures, we will examine specific circuits that control the vagus nerve and its effects on the gut. These experiments will be performed on a rat model of PD that uses paraquat and lectins orally. The objective of these experiments is to fully characterize the maladaptive plasticity so that experimental approaches can be tried to mitigate its adverse effects. In experiments we have published recently, we have shown that PD patients treated with a novel potential medication called squalamine improved gut motility and their PD rating scales for disability, suggesting that maladaptive neuronal plasticity can be corrected to benefit PD patients. Squalamine also has proven ability to clear pathological alpha synuclein from the gut. Thus, our aims will be to (1) fully characterize the maladaptive nigrovagal circuit plasticity and its effects on gut motility and sleep disorders associated with parkinsonism, (2) use specialized techniques to specifically target one hemisphere of the brain for neuroprotection in comparison with the other hemisphere in the same animal where degeneration proceeds unimpeded, and (3) test whether squalamine will mitigate non-motor symptoms such as gut dysmotility and sleep dysfunction in addition to impeding the progression of PD. These experiments will provide proof of concept for clinical translation of basic science discoveries that may provide enormous benefits to patients with PD, especially early in their disease, to protect them from disease progression.

These experiments target the FY20 Focus Areas of the DOD Neurotoxin Exposure Treatment Parkinson's program: 'Basic biology of non-motor symptoms that could lead to the development of new treatments for Parkinson's disease following neurotoxin exposure' and 'System-level mechanism of dopamine refractory motor symptoms in Parkinson's disease, including postural instability, freezing of gait, and treatment-associated dystonia, that could lead to development of new treatments in patients with neurotoxin exposure.' Our experiments will provide the first proof of concept for clinical application of basic science discoveries related to maladaptive nigrovagal plasticity for non-motor symptoms of PD with the focus on gut motility and sleep disorders.