How can rAAV-α-synuclein and the fibril α-synuclein models advance our understanding of Parkinson's disease?

Abstract

Animal models of Parkinson's disease (PD) are important for understanding the mechanisms of the disease and can contribute to developing and validating novel therapeutics. Ideally, these models should replicate the cardinal features of PD, such as progressive neurodegeneration of catecholaminergic neurons and motor defects. Many current PD models emphasize pathological forms of α-synuclein, based on findings that autosomal dominant mutations in α-synuclein and duplications/triplications of the SNCA gene cause PD. In addition, Lewy bodies and Lewy neurites, primarily composed of α-synuclein, represent the predominant pathological characteristics of PD. These inclusions have defined features, such as insolubility in non-ionic detergent, hyperphosphorylation, proteinase K sensitivity, a filamentous appearance by electron microscopy, and β-sheet structure. Furthermore, it has become clear that Lewy bodies and Lewy neurites are found throughout the peripheral and central nervous system, and could account not only for motor symptoms, but also for non-motor symptoms of the disease. The goal of this review is to describe two new α-synuclein-based models: the recombinant adeno-associated viral vector-α-synuclein model and the α-synuclein fibril model. An advantage of both models is that they do not require extensive crossbreeding of rodents transgenic for α-synuclein with other rodents transgenic for genes of interest to study the impact of such genes on PD-related pathology and phenotypes. In addition, abnormal α-synuclein can be expressed in brain regions relevant for disease. Here, we discuss the features of each model, how each model has contributed thus far to our understanding of PD, and the advantages and potential caveats of each model. This review describes two α-synuclein-based rodent models of Parkinson's disease: the rAAV-α-synuclein model and the α-synuclein fibril model. The key features of these models are described, and the extent to which they recapitulate features of PD, such as α-synuclein inclusion formation, loss of dopaminergic synapses in the striatum, motor defects, inflammation, and dopamine neuron death. This article is part of a special issue on Parkinson disease.

Keywords: AAV; Lewy bodies; Lewy neurites; Parkinson's disease; fibril; α-synuclein.

Fig. 1

Representative images of a mouse substantia nigra pars compacta transduced with rAAV2-CBΑ-synuclein-IRES-EGFP-WPRE. (a) The eGFP shows neurons transduced with rAAV2-α-synuclein and the magenta image shows tyrosine hydroxylase-positive neurons. Scale bar = 100 µm. B) The eGFP shows neurons transduced with rAAV2-α-synuclein, the magenta image shows tyrosine hydroxylase-positive neurons, and the blue shows major histocompatibility complex II (MHCII)-positive activated microglia near α-synuclein expressing neurons. Unpublished data. Scale bar = 50 µm.

Fig. 2

Injections of fibrils into the substantia nigra pars compacta induces the formation of pS129-α-synuclein inclusions with morphologies similar to Lewy bodies and Lewy neurites found in PD. Twenty micrograms of fibrils were injected into the substantia nigra pars compacta in 12-week-old male rats. After 4 weeks, animals were perfused and immunohistochemistry was performed for pS129-α-synuclein by DAB staining with Nissl counter-stain. (a) Representative image of the SNpc showing inclusions in the soma and neurites Scale bar is 30 µm). (b) Higher magnification of (a) showing the typical morphologies of pS129-α-synuclein inclusions in the SNpc neurons. The inclusions ranged from puncta in the soma to dense, spherical inclusions (c) Abundant Lewy-neurite-like inclusions in the amygdala. Unpublished data.