Animal Model for Prodromal Parkinson's Disease

Abstract

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and subsequent motor symptoms, but various non-motor symptoms (NMS) often precede motor symptoms. Recently, NMS have attracted much attention as a clue for identifying patients in a prodromal stage of PD, which is an excellent point at which to administer disease-modifying therapies (DMTs). These prodromal symptoms include olfactory loss, constipation, and sleep disorders, especially rapid eye movement sleep behavior disorder (RBD), all of which are also important for elucidating the mechanisms of the initiation and progression of the disease. For the development of DMTs, an animal model that reproduces the prodromal stage of PD is also needed. There have been various mammalian models reported, including toxin-based, genetic, and alpha synuclein propagation models. In this article, we review the animal models that exhibit NMS as prodromal symptoms and also discuss an appropriate prodromal model and its importance for the development of DMT of PD.

Keywords: Parkinson’s disease; alpha synuclein; animal model; prodromal.

Figure 1

Human Parkinson’s disease (PD) and mouse model in a prodromal stage. (A) In human PD, Lewy pathology is already present in a prodromal stage in extra central nervous system (CNS) tissues including GI tract and autonomic nerves, and in the lower brainstem and/or olfactory bulb. As a prodromal symptom hyposmia, constipation, and rapid eye movement sleep behavior disorder (RBD) appear in a chronologically close period, suggestive of the multifocal initiation of PD. Black dots indicate Lewy pathology. Bold red arrows and question marks indicates hypothesized propagation pathway of Lewy pathology in human. (B) In a propagation model, α-syn aggregates start from the olfactory bulb or the GI tract/ dorsal nucleus of the vagus nerve (DMV), and hyposmia and GI dysfunction appear as its corresponding symptoms in a prodromal stage. In contrast, in a α-syn BAC transgenic model that mildly overexpresses α-syn in its native expression manner, both of hyposmia and RBD are observed with multifocal accumulation of phosphorylated α-syn. Orange dots indicate accumulateon of phosphorylated α-syn and bold blue arrows indicate entry zone of injected α-syn. Thin solid arrows shows main propagateon pathway of α-syn and dotted arrows indicate minor propagateon pathway in animal experiments.