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.

Developmental Changes in Dendritic Spine Morphology in the Striatum and Their Alteration in an A53T α-Synuclein Transgenic Mouse Model of Parkinson’s Disease

“…In A53T-BAC-SNCA mice, a significant decrease in the number of tyrosine hydroxylase (TH)-positive dopaminergic cells in the substantia nigra is observed at 9 and 18 months, but not at 3 months (Taguchi et al, 2020a). This observation supports the prevailing idea that the onset of synaptic abnormalities and prodromal symptoms of PD precede the degeneration of dopaminergic cells and consequent manifestation of motor symptoms (Guidetti et al, 2001;Klapstein et al, 2001;Taguchi et al, 2020b). In future, it will be important to explore if distinct subcellular mechanisms are involved in the pathologies of the early prodromal stage and advanced, clinical stage of PD, and whether the former depends on the structural changes that occur at the synaptic level and the latter depends on the significant degeneration of dopaminergic cells in the basal ganglia.…”

“…It is crucial to mention that A53T-BAC-SNCA mice that we have used in this study recapitulate the symptoms and pathologies of prodromal PD (Taguchi et al, 2020a). Various non-motor related neurological abnormalities associated with prodromal PD are already evident as early as 2-3 months of age in the mouse models that mimics prodromal PD (Paumier et al, 2013;Taguchi et al, 2020b), but the gross motor dysfunctions appear much later in life coinciding with the significant degeneration of dopaminergic neurons (Taguchi et al, 2020b). In A53T-BAC-SNCA mice, a significant decrease in the number of tyrosine hydroxylase (TH)-positive dopaminergic cells in the substantia nigra is observed at 9 and 18 months, but not at 3 months (Taguchi et al, 2020a).…”

Parkinson’s Disease and the Gut: Future Perspectives for Early Diagnosis

“…Toxin-induced models are widely used models mainly due to the relatively simple use of the toxin, clear phenotype, the rapid onset of motor or non-motor symptoms of the disease and the ability to reflect motor complications of antiparkinsonian drugs, such as L-DOPA-induced dyskinesia (Morin et al, 2014;Taguchi et al, 2020b). The disadvantage is the exposure of experimenters to toxins, the frequent criticism that the concentrations used to induce PD-related symptoms do not commonly occur in the natural environment, but in particular that robust motor phenotypes may interfere with the analysis of non-motor symptoms (Taguchi et al, 2020b).…”

“…In these models, we must not forget that the choice of promoter fully influences the observed phenotype, whether in terms of the level of expression or the regions in which this gene will be expressed. A disadvantage compared to toxic models is the slower onset of the phenotype, and also that only a few models show loss of DA neurons and an associated motor phenotype (Taguchi et al, 2020b). Nevertheless, these models can significantly contribute not only to the understanding of PD-related pathomechanisms but also in the development of symptomatic or disease-modifying therapies that target non-motor symptoms associated with the disease.…”

Editorial for the Special Issue “Animal Models of Parkinson’s Disease and Related Disorders”

“…These phenotypes are particularly important in developing disease-modifying therapies that prevent the onset or control progression of PD. Taguchi et al [ 10 ] reviewed the current animal models that would reproduce the prodromal symptoms. Progress of PD is often accompanied by depression.…”