Experimental Animal Models of Prodromal Parkinson's Disease

Abstract

There is an estimated 35-45% loss of striatal dopamine at the time of diagnosis of Parkinson's disease (PD), and cases clinically diagnosed in the early stages may already be pathologically in advanced stages. Recent large-scale clinical trials of disease-modifying therapies (DMT) also suggest the necessity of targeting patients at earlier stages of the disease. From this perspective, the prodromal phase of PD is currently the focus of attention, emphasizing the need for a prodromal mouse model that accurately reflects the pathophysiology, along with early biomarkers. To establish prodromal animal model of PD with high face validity that reflects the disease state, the model must possess high construct validity that accurately incorporates clinical and pathological features in the prodromal phase. Furthermore, as a preclinical model of DMT, the model must possess high predictive validity to accurately evaluate the response to intervention. This review provides an overview of animal models which reflect the characteristics of prodromal PD, including alpha-synuclein (aS) accumulation and associated early non-motor symptoms, with a focus on the aS propagation model and genetic model. In addition, we discuss the challenges associated with these models. The genetic model often fails to induce motor symptoms, while aS propagation models skip the crucial step of initial aS aggregate formation, thereby not fully replicating the entire natural course of the disease. Identifying factors that induce the transition from prodromal to symptomatic phase is important as a preclinical model for DMT to prevent or delay the onset of the disease.

Keywords: Parkinson’s disease; animal model; disease-modifying therapy; non-motor; preclinical model; prodromal; prodromal Parkinson’s disease; propagation; synuclein; transgenic.

Fig. 1

Representative animal models of prodromal PD. The genetic model represented by the aS overexpression model focuses on disease onset but fails to show motor symptoms associated with DA cell loss. While most successful aS propagation models exhibit robust propagation and DA cell loss, they often skip the critical initial step of aS aggregate formation. Thus, the entire natural course of the disease, from the prodromal to the symptomatic phase, is not fully replicated by a single animal model. This limitation is one of the drawbacks as a preclinical model for DMT, targeting the inhibition of progression from the prodromal to symptomatic phase of PD. aS, alpha-synuclein; DA, dopamine; GI, gastrointestinal; PD, Parkinson’s disease; PFF, preformed fibrils; RBD, REM sleep behavior disorder.