Nathalie Van Den Berge, October 2018
Main supervisor: Per Borghammer, MD, PhD, DMSc, Professor
Parkinson’s disease (PD) is a degenerative and progressive disorder of the autonomic (ANS) and central nervous system (CNS). The main symptoms of PD are tremor at rest, slow movements, stiffness, and balance problems. Therefore, PD is classified as a motor system disorder. The PD-symptoms are caused by the loss of dopamine-producing cells located in the substantia nigra. Recently, it has been hypothesized that PD initiates in the periphery years before the first symptoms occur (“body-first” hypothesis), after which it extends to the CNS via peripheral autonomic nerves in a prion-like fashion. As the disease progresses, the severity of lesions in the areas affected and the amount of areas affected increases. This hypothesis might explain why PD patients frequently report a wide range of non-motor symptoms related to dysfunction of the peripheral nervous system (PNS). These non-motor symptoms appear up to 20 years prior to PD motor symptoms. Since no disease modifying therapy is currently available, these recent findings have important implications for early therapeutic intervention. It is widely believed that effective protective treatments must be instigated in the presymptomatic stage of PD. Experiments in humans, with the purpose of developing new therapies, are difficult and restricted due to ethical problems, and the necessity of large and homogeneous patient groups. Therefore, studies in animal models of PD are indispensable.
The goal of this project is twofold. First, we aim to develop a preclinical rat model of prodromal or presymptomatic PD, as this will teach us how PD pathology spreads from the periphery to the brain. In order to achieve this, we will inject aggregated protein in the gut and map the route of spreading (parasympathetic and sympathetic) by means of histology (see Fig. 1), Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), and autoradiography. Second, we aim to develop alpha-synuclein-PET and 18F-dopamine-PET as potential biomarkers for early diagnosis of prodromal PD in the established rodent model. A preclinical model of prodromal PD will enable highly important investigation of new diagnostic biomarkers and therapeutic strategies targeting the mechanism responsible for cell-to-cell spreading of pathology.
Figure 1. (A) Schematic overview showing the route of spreading of pathological alpha-synuclein along the parasympathetic and sympathetic pathway from gut to brain, after gastrointestinal challenge with preformed alpha-synuclein fibrils. (B) Immunohistochemical analysis shows pathological alpha-synuclein in the dorsal motor nucleus of the vagus (DMV), Locus Coeruleus (LC), Interomediolateral nucleus (IML), sympathetic ganglia, and duodenum of transgenic rats (that overexpress endogenous alpha-synuclein), after gastrointestinal injection of preformed alpha-synuclein fibrils (left column), and not in rats injected with saline (right column). Pathological accumulations of phosphorylated alpha-synuclein are detected by the use of Ab51253 antibody.